Статті в журналах: "RIOK2"

1

Wang, Jing, Thibault Varin, Michal Vieth, and Jonathan M. Elkins. "Crystal structure of human RIOK2 bound to a specific inhibitor." Open Biology 9, no. 4 (April 2019): 190037. http://dx.doi.org/10.1098/rsob.190037.

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The RIO kinases (RIOKs) are a universal family of atypical kinases that are essential for assembly of the pre-40S ribosome complex. Here, we present the crystal structure of human RIO kinase 2 (RIOK2) bound to a specific inhibitor. This first crystal structure of an inhibitor-bound RIO kinase reveals the binding mode of the inhibitor and explains the structure–activity relationship of the inhibitor series. The inhibitor binds in the ATP-binding site and forms extensive hydrophobic interactions with residues at the entrance to the ATP-binding site. Analysis of the conservation of active site residues reveals the reasons for the specificity of the inhibitor for RIOK2 over RIOK1 and RIOK3, and it provides a template for inhibitor design against the human RIOK family.

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2

Ghosh, Shrestha, Mahesh Raundhal, Samuel A. Myers, Steven A. Carr, Xi Chen, Gregory A. Petsko, and Laurie H. Glimcher. "Atypical Kinase RIOK2 Is a Master Regulator of Hematopoietic Cell Fate." Blood 138, Supplement 1 (November 5, 2021): 300. http://dx.doi.org/10.1182/blood-2021-149779.

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Abstract Here we report the discovery of a new master regulator of cell fate during hematopoietic differentiation, one whose function has major implications for the treatment of blood disorders such as anemia. Anemia is a major comorbidity in aging, chronic diseases such as renal failure and inflammation, bone marrow failure disorders and in hematologic neoplasms such as myelodysplastic syndromes (MDS), affecting roughly one third of the world population. Anemia is also often diagnosed in patients treated with chemotherapy or other cytotoxic agents. The comorbidities of peripheral blood cytopenias especially in elderly patients with MDS often outweigh the treatment benefits from allogeneic stem cell transplants leaving only a handful of FDA-approved drugs/therapies for treatment of such disorders. There is thus a dire need to revisit the origins of hematopoietic differentiation defects underlying these hematologic disorders to identify additional targets for novel therapies in treating anemia. We present evidence establishing that right open reading frame kinase 2 (RIOK2), an understudied atypical kinase associated with pre-40S ribosome biogenesis (Ferreira-Cerca et al., Nat. Str. Biol. 2012), is also a master transcriptional regulator of hematopoietic lineage commitment that simultaneously drives erythroid differentiation and represses myeloid and megakaryocytic lineages. We show that ablation of RIOK2 expression leads to hematopoietic differentiation defects in primary human hematopoietic stem and progenitor cells, the cells of origin for hematologic neoplasms. We identity RIOK2 as an integral player in governing major blood cell differentiation processes: erythropoiesis, megakaryopoiesis and myelopoiesis. Analyses in primary human CD34+ hematopoietic stem and progenitor cells (HSPCs) revealed that CRISPR/Cas9-mediated depletion of RIOK2 led to impaired erythropoiesis and a concomitant elevation in megakaryopoiesis and myelopoiesis. A more comprehensive analysis revealed that RIOK2 regulates the transcriptomic profiles of several key transcription factors that determine hematopoietic cell fate, including GATA1, GATA2, SPI1, RUNX3 and KLF1. Most importantly, we also observed a significant correlation between mRNA levels of RIOK2 and GATA1, GATA2, RUNX3 and KLF1 in MDS patient-derived bone marrow cells. We also demonstrate that loss of RIOK2 causes massive alterations in chromatin accessibility, both globally and specifically at the promoters of its putative target genes. This places RIOK2 at the apex of a transcriptional regulatory network controlling hematopoietic differentiation. We identify a previously unappreciated DNA-binding winged helix-turn-helix (wHTH) domain in RIOK2 conferring the protein with the properties and activities of a transcription factor. Transcriptomic profiling, structural modeling, chromatin immunoprecipitation-sequencing and a range of domain-deleted mutants reveal that RIOK2 functions as a bona-fide master transcription factor in hematopoiesis. We also identify two transactivation domains within the wHTH motif of RIOK2 that play integral roles in associating with the core transcriptional complex at promoter regions of genes. To the best of our knowledge, we present the first evidence of a protein that not only controls 40S ribosome biogenesis governing translation but also functions in the nucleus as a master transcription factor by regulating the expression of key transcription factors that determine hematopoietic cell fate. Our discovery of a novel master transcriptional regulator governing a multitude of hematopoietic lineages significantly advances our current understanding of the transcriptomic landscape underlying hematopoietic differentiation. We hope that our findings may lead to new approaches to target these newly identified regulatory networks in hematopoiesis that may be relevant not just for malignancies, but for other hematologic disorders as well, such as the anemia of aging, chronic and inflammatory diseases and aplastic anemias. We are hopeful that this study will also lay a foundation to discovering how proteins, like RIOK2, may integrate transcriptional processes with translational outcomes to drive cellular functions. Disclosures Raundhal: Jnana Therapeutics: Current Employment. Petsko: Amicus Therapeutics, MeiraGTx, Annovis Bio, Retromer Therapeutics, and Proclara Bioscience: Membership on an entity's Board of Directors or advisory committees; Denali Therapeutics, MeiraGTx, Annovis Bio, Retromer Therapeutics and Proclara Biosciences: Current equity holder in publicly-traded company. Glimcher: Kaleido Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Other: Former Director; Repare Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Abpro Therapeutics: Membership on an entity's Board of Directors or advisory committees.

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3

Cerezo, Emilie L., Thibault Houles, Oriane Lié, Marie-Kerguelen Sarthou, Charlotte Audoynaud, Geneviève Lavoie, Maral Halladjian, et al. "RIOK2 phosphorylation by RSK promotes synthesis of the human small ribosomal subunit." PLOS Genetics 17, no. 6 (June 14, 2021): e1009583. http://dx.doi.org/10.1371/journal.pgen.1009583.

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Ribosome biogenesis lies at the nexus of various signaling pathways coordinating protein synthesis with cell growth and proliferation. This process is regulated by well-described transcriptional mechanisms, but a growing body of evidence indicates that other levels of regulation exist. Here we show that the Ras/mitogen-activated protein kinase (MAPK) pathway stimulates post-transcriptional stages of human ribosome synthesis. We identify RIOK2, a pre-40S particle assembly factor, as a new target of the MAPK-activated kinase RSK. RIOK2 phosphorylation by RSK stimulates cytoplasmic maturation of late pre-40S particles, which is required for optimal protein synthesis and cell proliferation. RIOK2 phosphorylation facilitates its release from pre-40S particles and its nuclear re-import, prior to completion of small ribosomal subunits. Our results bring a detailed mechanistic link between the Ras/MAPK pathway and the maturation of human pre-40S particles, which open a hitherto poorly explored area of ribosome biogenesis.

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4

Asquith, Christopher R. M., Michael P. East, and William J. Zuercher. "RIOK2: straddling the kinase/ATPase line." Nature Reviews Drug Discovery 18, no. 8 (June 26, 2019): 574. http://dx.doi.org/10.1038/d41573-019-00107-7.

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5

Yu, Min, Xiaoyan Hu, Jingyu Yan, Ying Wang, Fei Lu, and Junlei Chang. "RIOK2 Inhibitor NSC139021 Exerts Anti-Tumor Effects on Glioblastoma via Inducing Skp2-Mediated Cell Cycle Arrest and Apoptosis." Biomedicines 9, no. 9 (September 17, 2021): 1244. http://dx.doi.org/10.3390/biomedicines9091244.

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Up to now, the chemotherapy approaches for glioblastoma were limited. 1-[2-Thiazolylazo]-2-naphthol (named as NSC139021) was shown to significantly inhibit the proliferation of prostate cancer cells by targeting the atypical protein kinase RIOK2. It is documented that RIOK2 overexpressed in glioblastoma. However, whether NSC139021 can inhibit the growth of glioblastoma cells and be a potential drug for glioblastoma treatment need to be clarified. In this study, we investigated the effects of NSC139021 on human U118MG, LN-18, and mouse GL261 glioblastoma cells and the mouse models of glioblastoma. We verified that NSC139021 effectively inhibited glioblastoma cells proliferation, but it is independent of RIOK2. Our data showed that NSC139021 induced cell cycle arrest at G0/G1 phase via the Skp2-p27/p21-Cyclin E/CDK2-pRb signaling pathway in G1/S checkpoint regulation. In addition, NSC139021 also increased the apoptosis of glioblastoma cells by activating the p53 signaling pathway and increasing the levels of Bax and cleaved caspase 3. Furthermore, intraperitoneal administration of 150 mg/kg NSC139021 significantly suppressed the growth of human and mouse glioblastoma in vivo. Our study suggests that NSC139021 may be a potential chemotherapy drug for the treatment of glioblastoma by targeting the Skp2-p27/p21-Cyclin E/CDK2-pRb signaling pathway.

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6

Chen, Alexander, and Renee Read. "CSIG-11. UNDERSTANDING THE MECHANISM OF RIOK2 FUNCTION IN GLIOBLASTOMA." Neuro-Oncology 20, suppl_6 (November 2018): vi45. http://dx.doi.org/10.1093/neuonc/noy148.177.

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7

Chen, Alexander, and Renee Read. "CSIG-16. UNDERSTANDING THE MECHANISM OF RIOK2 FUNCTION IN GLIOBLASTOMA." Neuro-Oncology 19, suppl_6 (November 2017): vi53. http://dx.doi.org/10.1093/neuonc/nox168.210.

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8

Ghosh, Shrestha, Mahesh Raundhal, Samuel A. Myers, Steven A. Carr, Xi Chen, Gregory A. Petsko, and Laurie H. Glimcher. "Identification of RIOK2 as a master regulator of human blood cell development." Nature Immunology 23, no. 1 (December 22, 2021): 109–21. http://dx.doi.org/10.1038/s41590-021-01079-w.

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9

Boyd, Nathaniel, Alexander Chen, Jhomar Marquez, and Renee Read. "CSIG-04. A REQUIREMENT FOR RIOK2 CATALYTIC ACTIVITY IN RTK-PI3K DEPENDENT GLIOBLASTOMA." Neuro-Oncology 20, suppl_6 (November 2018): vi43. http://dx.doi.org/10.1093/neuonc/noy148.170.

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10

Song, Yunnong, Cheng Li, Lei Jin, Jingsong Xing, Zhuang Sha, Tong Zhang, Daofei Ji, Rutong Yu, and Shangfeng Gao. "RIOK2 is negatively regulated by miR‐4744 and promotes glioma cell migration/invasion through epithelial‐mesenchymal transition." Journal of Cellular and Molecular Medicine 24, no. 8 (March 3, 2020): 4494–509. http://dx.doi.org/10.1111/jcmm.15107.

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11

Chen, Zhong-ping, Jing Wang, Qun-ying Yang, and Jing Zeng. "EPCO-34. CLINICAL AND GENETIC EVOLUTION OF EPENDYMOMA." Neuro-Oncology 22, Supplement_2 (November 2020): ii76. http://dx.doi.org/10.1093/neuonc/noaa215.313.

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Abstract Ependymomas are glial brain tumors accounting for approximately 2~3% of all primary tumors in central nervous system (CNS), and 12% of all pediatric intracranial tumors. To better understand the evolution process of ependymomas, we studied the clinical, pathological and genetic development of a rare girl case with repeatedly recurrent ependymoma. This girl was diagnosed as anaplastic ependymoma at age of 9 years old, and experienced 7 times tumor relapse and received 9 times surgeries but finally ceased at19 years old with multiregional recurrences. The pathological characteristics, radiographic images and therapeutic strategies of the patient were all retrieved. Molecular markers confirmed the diagnosis based on the updated WHO guideline for CNS tumors. Whole-genome sequencing (WGS) was performed to elucidate the landscape of mutation signatures and to identify potential driver mutations along the tumor progression. The seven tumor specimens showed a highly branched evolutionary pattern. There were six gene mutations found in 5 of the 7 specimens (PCDHA4, PCDHA8, SEC14L6, SETD2, RIOK2, and SLCO2A1) and three in 6 of 7 the samples (RYR1, SNX25, DSC2). Strikingly, there was one gene, ADGRL3, which was found to be consistently mutated in the entire disease progression process. Our findings therefore suggest that ADGRL3 might play roles in the disease progression of ependymoma patient.

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12

Chen, Zhong-ping, Jing Wang, Shao-yan Xi, Qi Zhao, Yun-fei Xia, Cheng-cheng Guo, Qun-ying Yang, et al. "EPEN-05. CLINICAL AND GENETIC EVOLUTION OF EPENDYMOMA EXPOSED FROM A MULTI-RECURRENCE GIRL CASE." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii308—iii309. http://dx.doi.org/10.1093/neuonc/noaa222.146.

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Abstract Ependymomas are glial brain tumors accounting for approximately 2~3% of all primary tumors of the central nervous system (CNS), and 12% of all pediatric intracranial tumors. To better understand the evolution process of ependymomas, we studied the clinical, pathological and genetic development of a rare girl case with repeatedly recurrent ependymoma. This girl was diagnosed as ependymoma at age of 9 years old, and experienced 7 times tumor relapse and received 9 times surgeries but finally ceased at 19 years old with multiregional recurrences. The pathological characteristics, radiographic images and therapeutic strategies of the patient were all retrieved. Molecular markers confirmed the diagnosis of anaplastic ependymoma based on the updated WHO guideline for CNS tumors. Whole-genome sequencing (WGS) was performed to elucidate the landscape of mutation signatures and to identify potential driver mutations along the tumor progression. The seven tumor specimens showed a highly branched evolutionary pattern. There were six gene mutations found in 5 of the 7 specimens (PCDHA4, PCDHA8, SEC14L6, SETD2, RIOK2, and SLCO2A1) and three in 6 of 7 the samples (RYR1, SNX25, DSC2). Strikingly, there was one gene, ADGRL3, which was found to be consistently mutated in the entire disease progression process. Our findings therefore suggest that ADGRL3 might play roles in the disease progression of ependymoma patient.

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13

Bailly, Christian. "Anticancer Activities and Mechanism of Action of Nagilactones, a Group of Terpenoid Lactones Isolated from Podocarpus Species." Natural Products and Bioprospecting 10, no. 6 (October 9, 2020): 367–75. http://dx.doi.org/10.1007/s13659-020-00268-8.

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Abstract Nagilactones are tetracyclic natural products isolated from various Podocarpus species. These lactone-based compounds display a range of pharmacological effects, including antifungal, anti-atherosclerosis, anti-inflammatory and anticancer activities reviewed here. The most active derivatives, such as nagilactones C, E and F, exhibit potent anticancer activities against different cancer cell lines and tumor models. A comprehensive analysis of their mechanism of action indicates that their anticancer activity mainly derives from three complementary action: (i) a drug-induced inhibition of cell proliferation coupled with a cell cycle perturbation and induction of apoptosis, (ii) a blockade of the epithelial to mesenchymal cell transition contributing to an inhibition of cancer cell migration and invasion and (iii) a capacity to modulate the PD-L1 immune checkpoint. Different molecular effectors have been implicated in the antitumor activity, chiefly the AP-1 pathway blocked upon activation of the JNK/c-Jun axis. Nag-C is a potent inhibitor of protein synthesis binding to eukaryotic ribosomes and inhibition of different protein kinases, such as RIOK2 and JAK2, has been postulated with Nag-E. The literature survey on nagilactones highlights the therapeutic potential of these little-known terpenoids. The mechanistic analysis also provides useful information for structurally related compounds (podolactones, oidiolactones, inumakilactones) isolated from Podocarpus plants.

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14

Subbannayya, Yashwanth, Markus Haug, Sneha M. Pinto, Varshasnata Mohanty, Hany Zakaria Meås, Trude Helen Flo, T. S. Keshava Prasad, and Richard K. Kandasamy. "The Proteomic Landscape of Resting and Activated CD4+ T Cells Reveal Insights into Cell Differentiation and Function." International Journal of Molecular Sciences 22, no. 1 (December 29, 2020): 275. http://dx.doi.org/10.3390/ijms22010275.

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CD4+ T cells (T helper cells) are cytokine-producing adaptive immune cells that activate or regulate the responses of various immune cells. The activation and functional status of CD4+ T cells is important for adequate responses to pathogen infections but has also been associated with auto-immune disorders and survival in several cancers. In the current study, we carried out a label-free high-resolution FTMS-based proteomic profiling of resting and T cell receptor-activated (72 h) primary human CD4+ T cells from peripheral blood of healthy donors as well as SUP-T1 cells. We identified 5237 proteins, of which significant alterations in the levels of 1119 proteins were observed between resting and activated CD4+ T cells. In addition to identifying several known T-cell activation-related processes altered expression of several stimulatory/inhibitory immune checkpoint markers between resting and activated CD4+ T cells were observed. Network analysis further revealed several known and novel regulatory hubs of CD4+ T cell activation, including IFNG, IRF1, FOXP3, AURKA, and RIOK2. Comparison of primary CD4+ T cell proteomic profiles with human lymphoblastic cell lines revealed a substantial overlap, while comparison with mouse CD+ T cell data suggested interspecies proteomic differences. The current dataset will serve as a valuable resource to the scientific community to compare and analyze the CD4+ proteome.

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15

Zhang, Wei, Chujing Zhang, Ruiqi Huang, Mengsheng Qiu, and Fei-xue Li. "Induction of right open reading frame kinase 3 (RIOK3) during ovulation and luteinisation in rat ovary." Reproduction, Fertility and Development 33, no. 16 (2021): 810. http://dx.doi.org/10.1071/rd21118.

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Atypical protein serine kinase RIOK3 is involved in cellular invasion and survival. The spatiotemporal expression pattern and regulatory mechanisms controlling expression of Riok3 were investigated in the rat ovary during the periovulatory period. Immature female rats (22–23 days old) were treated with pregnant mare’s serum gonadotropin (PMSG) to stimulate follicular development, followed 48h later by injection with human chorionic gonadotrophin (hCG). Ovaries, granulosa cells, or theca-interstitial cells were collected at various times after hCG administration. Both real-time polymerase chain reaction (PCR) and in situ hybridisation analysis revealed that Riok3 was highly induced in both granulosa cells and theca-interstitial cells by hCG. Riok3 expression was induced in theca-interstitial cells at 4h after hCG. However, the expression of Riok3 mRNA was stimulated in granulosa cells at 8h. Both protein kinase C inhibitor (GF109203) and the protein kinase A inhibitor (H89) could block the stimulation of Riok3 mRNA by hCG. Furthermore, Riok3 induction is dependent on new protein synthesis. Inhibition of prostaglandin synthesis or progesterone action did not alter Riok3 mRNA expression, whereas inhibition of the epidermal growth factor (EGF) pathway downregulated Riok3 expression. In conclusion, our findings suggest that the induction of the RIOK3 may be important for ovulation and luteinisation.

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16

Ellwanger, Kornelia, Selina Briese, Christine Arnold, Ioannis Kienes, Valentin Heim, Ueli Nachbur, and Thomas A. Kufer. "XIAP controls RIPK2 signaling by preventing its deposition in speck-like structures." Life Science Alliance 2, no. 4 (July 26, 2019): e201900346. http://dx.doi.org/10.26508/lsa.201900346.

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The receptor interacting serine/threonine kinase 2 (RIPK2) is essential for linking activation of the pattern recognition receptors NOD1 and NOD2 to cellular signaling events. Recently, it was shown that RIPK2 can form higher order molecular structures in vitro. Here, we demonstrate that RIPK2 forms detergent insoluble complexes in the cytosol of host cells upon infection with invasive enteropathogenic bacteria. Formation of these structures occurred after NF-κB activation and depended on the caspase activation and recruitment domain of NOD1 or NOD2. Complex formation upon activation required RIPK2 autophosphorylation at Y474 and was influenced by phosphorylation at S176. We found that the E3 ligase X-linked inhibitor of apoptosis (XIAP) counteracts complex formation of RIPK2, accordingly mutation of the XIAP ubiquitylation sites in RIPK2 enhanced complex formation. Taken together, our work reveals novel roles of XIAP in the regulation of RIPK2 and expands our knowledge on the function of RIPK2 posttranslational modifications in NOD1/2 signaling.

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17

Feng, Jun, Paul D. De Jesus, Victoria Su, Stephanie Han, Danyang Gong, Nicholas C. Wu, Yuan Tian, et al. "RIOK3 Is an Adaptor Protein Required for IRF3-Mediated Antiviral Type I Interferon Production." Journal of Virology 88, no. 14 (May 7, 2014): 7987–97. http://dx.doi.org/10.1128/jvi.00643-14.

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ABSTRACTDetection of cytosolic nucleic acids by pattern recognition receptors leads to the induction of type I interferons (IFNs) and elicits the innate immune response. We report here the identification of RIOK3 as a novel adaptor protein that is essential for the cytosolic nucleic acid-induced type I IFN production and for the antiviral response to gammaherpesvirus through two independent kinome-wide RNA interference screens. RIOK3 knockdown blocks both cytosolic double-stranded B-form DNA and double-stranded RNA-induced IRF3 activation and IFN-β production. In contrast, the overexpression of RIOK3 activates IRF3 and induces IFN-β. RIOK3 functions downstream of TBK1 and upstream of IRF3 activation. Furthermore, RIOK3 physically interacts with both IRF3 and TBK1 and is necessary for the interaction between TBK1 and IRF3. In addition, global transcriptome analysis shows that the expression of many gene involved antiviral responses is dependent on RIOK3. Thus, knockdown of RIOK3 inhibits cellular antiviral responses against both DNA and RNA viruses (herpesvirus and influenza A virus). Our data suggest that RIOK3 plays a critical role in the antiviral type I IFN pathway by bridging TBK1 and IRF3.IMPORTANCEThe innate immune response, such as the production of type I interferons, acts as the first line of defense, limiting infectious pathogens directly and shaping the adaptive immune response. In this study, we identified RIOK3 as a novel regulator of the antiviral type I interferon pathway. Specifically, we found that RIOK3 physically interacts with TBK1 and IRF3 and bridges the functions between TBK1 and IRF3 in the activation of type I interferon pathway. The identification of a cellular kinase that plays a role the type I interferon pathway adds another level of complexity in the regulation of innate immunity and will have implications for developing novel strategies to combat viral infection.

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18

Jaafar, Rola F., Zeid Ibrahim, Karim Ataya, Joelle Hassanieh, Natasha Ard, and Walid Faraj. "Receptor-Interacting Serine/Threonine-Protein Kinase-2 as a Potential Prognostic Factor in Colorectal Cancer." Medicina 57, no. 7 (July 14, 2021): 709. http://dx.doi.org/10.3390/medicina57070709.

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Background and objectives: Receptor-interacting serine/threonine-protein kinase-2 (RIPK2) is an important mediator in different pathways in the immune and inflammatory response system. RIPK2 was also shown to play different roles in different cancer types; however, in colorectal cancer (CRC), its role is not well established. This study aims at identifying the role of RIPK2 in CRC progression and survival. Materials and methods: Data of patients and mRNA protein expression level of genes associated with CRC (RIPK2, tumor necrosis factor (TNF), TRAF1, TRAF7, KLF6, interlukin-6 (Il6), interlukin-8 (Il8), vascular-endothelial growth factor A (VEGFA), MKI67, TP53, nuclear factor-kappa B (NFKB), NFKB2, BCL2, XIAP, and RELA) were downloaded from the PrognoScan online public database. Patients were divided between low and high RIPK2 expression and different CRC characteristics were studied between the two groups. Survival curves were evaluated using a Kaplan–Meier estimator. The Pearson correlation was used to study the correlation between RIPK2 and the other factors. Statistical analysis was carried out using SPSS version 25.0. The Human Protein Atlas was also used for the relationship between RIPK2 expression in CRC tissues and survival. Differences were considered statistically significant at p < 0.05. Results: A total of 520 patients were downloaded from the PrognoScan database, and RIPK2 was found to correlate with MKI67, TRAF1, KLF6, TNF, Il6, Il8, VEGFA, NFKB2, BCL2, and RELA. High expression of RIPK2 was associated with high expression of VEGFA (p < 0.01) and increased mortality (p < 0.01). Conclusions: In this study, RIPK2 is shown to be a potential prognostic factor in CRC; however, more studies are needed to assess and verify its potential role as a prognostic marker and in targeted therapy.

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Cavallari, Joseph F., Nicole G. Barra, Kevin P. Foley, Amanda Lee, Brittany M. Duggan, Brandyn D. Henriksbo, Fernando Forato Anhê, Ali A. Ashkar, and Jonathan D. Schertzer. "Postbiotics for NOD2 require nonhematopoietic RIPK2 to improve blood glucose and metabolic inflammation in mice." American Journal of Physiology-Endocrinology and Metabolism 318, no. 4 (April 1, 2020): E579—E585. http://dx.doi.org/10.1152/ajpendo.00033.2020.

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Defining the host receptors and metabolic consequences of bacterial components can help explain how the microbiome influences metabolic diseases. Bacterial peptidoglycans that activate nucleotide-binding oligomerization domain-containing (NOD)1 worsen glucose control, whereas NOD2 activation improves glycemia. Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) is required for innate immunity instigated by NOD1 and NOD2. The role of RIPK2 in the divergent effects of NOD1 versus NOD2 on blood glucose was unknown. We found that whole body deletion of RIPK2 negated all effects of NOD1 or NOD2 activation on blood glucose during an acute, low level endotoxin challenge in mice. It was known that NOD1 in hematopoietic cells participates in insulin resistance and metabolic inflammation in obese mice. It was unknown if RIPK2 in hematopoietic cells is required for the glucose-lowering and anti-inflammatory effects of NOD2 activation. We hypothesized that RIPK2 in nonhematopoietic cells dictated the glycemic effects of NOD2 activation. We found that whole body deletion of RIPK2 prevented the glucose-lowering effects of repeated NOD2 activation that were evident during a glucose tolerance test (GTT) in high-fat diet (HFD)-fed wild-type (WT) mice. NOD2 activation lowered glucose during a GTT and lowered adipose tissue inflammation in mice with RIPK2 deleted in hematopoietic cells. We conclude that RIPK2 in nonhematopoietic cells mediates the glucose lowering and anti-inflammatory effects of NOD2-activating postbiotics. We propose a model where lipopolysaccharides and NOD1 ligands synergize in hematopoietic cells to promote insulin resistance but NOD2 activation in nonhematopoietic cells promotes RIPK2-dependent immune tolerance and lowering of inflammation and insulin resistance.

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20

Sun, Bingqing, and Hongwen Zhao. "The bioinformatics analysis of RIOX2 gene in lung adenocarcinoma and squamous cell carcinoma." PLOS ONE 16, no. 12 (December 2, 2021): e0259447. http://dx.doi.org/10.1371/journal.pone.0259447.

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Lung cancer is characterized by high morbidity and mortality rates, and it has become an important public health issue worldwide. The occurrence and development of tumors is a multi-gene and multi-stage complex process. As an oncogene, ribosomal oxygenase 2 (RIOX2) has been associated with a variety of cancers. In this article, we analyzed the correlation between RIOX2 expression and methylation in lung cancer based on the databases including the cancer genome atlas (TCGA) (https://portal.gdc.cancer.gov/) and the gene expression omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/). It was found that RIOX2 is highly expressed in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tissues, whose expression is negatively correlated with its methylation level. In this regard, methylation at cg09716038, cg14773523, cg14941179, and cg22299097 had a significant negative correlation with RIOX2 expression in LUAD, whereas in LUSC, methylation at cg09716038, cg14773523, cg14941179, cg22299097, cg05451573, cg10779801, and cg23629183 is negatively correlated with RIOX2 expression. According to the analysis based on the databases, RIOX2 gene could not be considered as the independent prognostic biomarker in lung adenocarcinoma or squamous cell lung cancer. However, the molecular mechanism of RIOX2 gene in the development of lung cancer may be helpful in improving lung cancer therapy.

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21

Gao, Chenlin, Jiao Chen, Fang Fan, Yang Long, Shi Tang, Chunxia Jiang, Jiying Wang, Youhua Xu, and Yong Xu. "RIPK2-Mediated Autophagy and Negatively Regulated ROS-NLRP3 Inflammasome Signaling in GMCs Stimulated with High Glucose." Mediators of Inflammation 2019 (August 14, 2019): 1–13. http://dx.doi.org/10.1155/2019/6207563.

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Background. Hyperglycemia plays a vital role in diabetic nephropathy (DN); autophagy and its potential upregulator receptor-interacting protein kinase 2 (RIPK2) are associated with ROS, which play a potential role in regulating NLRP3, and may be involved in inflammation in DN. Aim. In this study, we aimed to explore the mechanisms mediated by RIPK2 in autophagy and the relationship with ROS-NLRP3 of DN, by investigating the levels of RIPK2 and autophagy in glomerular mesangial cells (GMCs) stimulated with high glucose. Material and Methods. GMCs were divided into the following groups: normal group (NC), high glucose group (HG), and RIPK2 siRNA group. RIPK2, LC3, caspase1, and IL-1β levels were measured by western blotting and RT-PCR. Autophagosomes were measured by GFP-RFP-LC3; ROS were detected by DCFH-DA. Results. High glucose upregulated RIPK2 and LC3 in GMCs during short periods (0-12 h) (p<0.01), while RIPK2 and LC3 were significantly downregulated in the long term (12-72 h) (p<0.01); these changes were positively correlated with glucose concentration (p<0.01). In addition, levels of ROS, caspase1, and IL-1β increased in a time- and dose-dependent manner in the high glucose group, even with an increased expression of LC3 (p<0.01). However, LC3 expression decreased in the siRIPK2 group, while levels of ROS, caspase1, and IL-1β increased (p<0.01). Conclusions. Autophagy was activated by high glucose at short time periods but was inhibited in the long term, demonstrating a dual role for high glucose in autophagy of GMCs. RIPK2 regulates ROS-NLRP3 inflammasome signaling through autophagy and may be involved in the pathogenesis of DN.

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Fang, Hong, Xiao Man Wu, Yi Wei Hu, Yun Jie Song, Jie Zhang, and Ming Xian Chang. "NLRC3-like 1 inhibits NOD1-RIPK2 pathway via targeting RIPK2." Developmental & Comparative Immunology 112 (November 2020): 103769. http://dx.doi.org/10.1016/j.dci.2020.103769.

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Havranek, Katherine E., Luke Adam White, Thomas C. Bisom, Jean-Marc Lanchy, and J. Stephen Lodmell. "The Atypical Kinase RIOK3 Limits RVFV Propagation and Is Regulated by Alternative Splicing." Viruses 13, no. 3 (February 26, 2021): 367. http://dx.doi.org/10.3390/v13030367.

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In recent years, transcriptome profiling studies have identified changes in host splicing patterns caused by viral invasion, yet the functional consequences of the vast majority of these splicing events remain uncharacterized. We recently showed that the host splicing landscape changes during Rift Valley fever virus MP-12 strain (RVFV MP-12) infection of mammalian cells. Of particular interest, we observed that the host mRNA for Rio Kinase 3 (RIOK3) was alternatively spliced during infection. This kinase has been shown to be involved in pattern recognition receptor (PRR) signaling mediated by RIG-I like receptors to produce type-I interferon. Here, we characterize RIOK3 as an important component of the interferon signaling pathway during RVFV infection and demonstrate that RIOK3 mRNA expression is skewed shortly after infection to produce alternatively spliced variants that encode premature termination codons. This splicing event plays a critical role in regulation of the antiviral response. Interestingly, infection with other RNA viruses and transfection with nucleic acid-based RIG-I agonists also stimulated RIOK3 alternative splicing. Finally, we show that specifically stimulating alternative splicing of the RIOK3 transcript using a morpholino oligonucleotide reduced interferon expression. Collectively, these results indicate that RIOK3 is an important component of the mammalian interferon signaling cascade and its splicing is a potent regulatory mechanism capable of fine-tuning the host interferon response.

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Mughal, Mudassar, Qing Ye, Lu Zhao, Christoph Grevelding, Ying Li, Wenda Di, Xin He, Xuesong Li, Robin Gasser, and Min Hu. "First Evidence of Function for Schistosoma japonicum riok-1 and RIOK-1." Pathogens 10, no. 7 (July 8, 2021): 862. http://dx.doi.org/10.3390/pathogens10070862.

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Protein kinases are known as key molecules that regulate many biological processes in animals. The right open reading frame protein kinase (riok) genes are known to be essential regulators in model organisms such as the free-living nematode Caenorhabditis elegans. However, very little is known about their function in parasitic trematodes (flukes). In the present study, we characterized the riok-1 gene (Sj-riok-1) and the inferred protein (Sj-RIOK-1) in the parasitic blood fluke, Schistosoma japonicum. We gained a first insight into function of this gene/protein through double-stranded RNA interference (RNAi) and chemical inhibition. RNAi significantly reduced Sj-riok-1 transcription in both female and male worms compared with untreated control worms, and subtle morphological alterations were detected in the ovaries of female worms. Chemical knockdown of Sj-RIOK-1 with toyocamycin (a specific RIOK-1 inhibitor/probe) caused a substantial reduction in worm viability and a major accumulation of mature oocytes in the seminal receptacle (female worms), and of spermatozoa in the sperm vesicle (male worms). These phenotypic alterations indicate that the function of Sj-riok-1 is linked to developmental and/or reproductive processes in S. japonicum.

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Pang, Y., S. Menzies, S. Baksh, and L. M. Sly. "A188 TARGETING RIPK2 TO TREAT INTESTINAL INFLAMMATION CAUSED BY SHIP DEFICIENCY." Journal of the Canadian Association of Gastroenterology 4, Supplement_1 (March 1, 2021): 204–5. http://dx.doi.org/10.1093/jcag/gwab002.186.

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Abstract Background Crohn’s disease (CD) is a form of inflammatory bowel disease characterized by chronic inflammation along the gastrointestinal tract. We have described the SHIP-/- mouse model of CD-like intestinal inflammation. SHIP-/- mice develop spontaneous ileal inflammation that is characterized by villus hyperplasia and disorganization, edema, immune cell infiltration, ulceration, loss of goblet cells, and muscle wall thickening. SHIP deficiency in people with CD has been associated with a more severe and treatment-refractory disease. Interestingly, NOD2 gene variants, which are the most profound genetic associations for CD, are also associated with a more severe CD phenotype. Muramyl dipeptide (MDP) is a molecular associated microbial pattern, which activates the NOD2 signalling pathway. Recently, SHIP has been reported to play a role in the NOD2 pathway by disrupting the downstream interaction between RIPK2 and XIAP required for NOD2-mediated NFκB activation and pro-inflammatory cytokine production. Aims Based on this, we hypothesized that SHIP deficiency contributes to inflammation in CD by increasing NOD2-mediated pro-inflammatory cytokine production. Moreover, RIPK2 inhibitors will block intestinal inflammation caused by SHIP deficiency by blocking RIPK2-XIAP interactions required for NOD2 signalling and resultant pro-inflammatory cytokine production. To test this hypothesis, my aim was to determine the effect of RIPK2 inhibitors on the development of spontaneous intestinal inflammation in SHIP-/- mice. Methods 6 week-old SHIP-/- mice (and SHIP+/+ mice controls) were treated with RIPK2 inhibitors, FCG806791773 or Z1210264067, by intra-pertioneal injections every other day for 2 weeks and compared to SHIP-/- mice treated with 2% DMSO in PBS, as a vehicle control. On Day 14, distal ilea were harvested and gross pathology was assessed. Cross-sections of the ilea were H&E stained to evaluate histological damage based on villi architecture, edema, immune cell infiltration, ulceration, goblet cell loss, and muscle wall thickening. Results As expected, SHIP+/+ mice did not have gut pathology and their healthy gut phenotype was not affected by RIPK2 inhibitors. SHIP-/- mice had ileal inflammation that was evident in gross pathology and in H&E-stained tissue sections. Importantly, SHIP-/- mice treated with RIPK2 inhibitors, FCG806791773 or Z1210264067, had reduced gross pathology compared to vehicle control-treated mice. Z1210264067 treated SHIP-/- mice also had significantly lower histological damage compared to vehicle control-treated SHIP-/- mice. Conclusions RIPK2 inhibitors reduced gross and histopathology in SHIP-/- mice suggesting that RIPK2 inhibitors may be an effective treatment for people with CD, and may be particularly effective in people with CD, who harbor NOD2 risk variants and/or have low SHIP activity. Funding Agencies CCC, CIHR

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Roos, Martin. "Hemmung des Enzyms RIOK1." Im Focus Onkologie 20, no. 7-8 (July 2017): 11. http://dx.doi.org/10.1007/s15015-017-3416-6.

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Takashima, Ken, Hiroyuki Oshiumi, and Tsukasa Seya. "RIOK3 keeps MDA5 inactive." Oncotarget 6, no. 31 (August 26, 2015): 30423–24. http://dx.doi.org/10.18632/oncotarget.5265.

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Fan, Yi-Hsin, Sujayita Roy, Rupkatha Mukhopadhyay, Arun Kapoor, Priya Duggal, Genevieve L. Wojcik, Robert F. Pass, and Ravit Arav-Boger. "Role of nucleotide-binding oligomerization domain 1 (NOD1) and its variants in human cytomegalovirus control in vitro and in vivo." Proceedings of the National Academy of Sciences 113, no. 48 (November 16, 2016): E7818—E7827. http://dx.doi.org/10.1073/pnas.1611711113.

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Induction of nucleotide-binding oligomerization domain 2 (NOD2) and downstream receptor-interacting serine/threonine-protein kinase 2 (RIPK2) by human cytomegalovirus (HCMV) is known to up-regulate antiviral responses and suppress virus replication. We investigated the role of nucleotide-binding oligomerization domain 1 (NOD1), which also signals through RIPK2, in HCMV control. NOD1 activation by Tri-DAP (NOD1 agonist) suppressed HCMV and induced IFN-β. Mouse CMV was also inhibited through NOD1 activation. NOD1 knockdown (KD) or inhibition of its activity with small molecule ML130 enhanced HCMV replication in vitro. NOD1 mutations displayed differential effects on HCMV replication and antiviral responses. In cells overexpressing the E56K mutation in the caspase activation and recruitment domain, virus replication was enhanced, but in cells overexpressing the E266K mutation in the nucleotide-binding domain or the wild-type NOD1, HCMV was inhibited, changes that correlated with IFN-β expression. The interaction of NOD1 and RIPK2 determined the outcome of virus replication, as evidenced by enhanced virus growth in NOD1 E56K mutant cells (which failed to interact with RIPK2). NOD1 activities were executed through IFN-β, given that IFN-β KD reduced the inhibitory effect of Tri-DAP on HCMV. Signaling through NOD1 resulting in HCMV suppression was IKKα-dependent and correlated with nuclear translocation and phosphorylation of IRF3. Finally, NOD1 polymorphisms were significantly associated with the risk of HCMV infection in women who were infected with HCMV during participation in a glycoprotein B vaccine trial. Collectively, our data indicate a role for NOD1 in HCMV control via RIPK2- IKKα-IRF3 and suggest that its polymorphisms predict the risk of infection.

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Li, Xingyu, Zhiqiang Li, Hongwei Zhu, and Xiao Yu. "Autophagy Regulatory Genes MET and RIPK2 Play a Prognostic Role in Pancreatic Ductal Adenocarcinoma: A Bioinformatic Analysis Based on GEO and TCGA." BioMed Research International 2020 (November 5, 2020): 1–15. http://dx.doi.org/10.1155/2020/8537381.

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Pancreatic ductal adenocarcinoma is a common malignant tumor with a poor prognosis. Autophagy activity changes in both cancer cells and microenvironment and affects the progression of pancreatic ductal adenocarcinoma. The purpose of this study was to predict the prognostic autophagy regulatory genes and their role in the regulation of autophagy in pancreatic ductal adenocarcinoma. We draw conclusions based on gene expression data from different platforms: GSE62165 and GSE85916 from the array platform, TCGA from the bulk RNA-seq platform, and GSE111672 from the single-cell RNA-seq platform. At first, we detected differentially expressed genes in pancreatic ductal adenocarcinoma compared with normal pancreatic tissue based on GSE62165. Then, we screened prognostic genes based on GSE85916 and TCGA. Furthermore, we constructed a risk signature composed of the prognostic differentially expressed genes. Finally, we predicted the probable role of these genes in regulating autophagy and the types of cell expressing these genes. According to our screening criteria, there were only two genes: MET and RIPK2, selected into the development of the risk signature. However, evaluated by log-rank tests, receiver operating characteristic curves, and calibration curves, the risk signature was worth considering its clinical application because of good sensitivity, specificity, and stability. Besides, we predicted that both MET and RIPK2 promote autophagy in pancreatic ductal adenocarcinoma by gene set enrichment analysis. Analysis of single-cell RNA-seq data from GSE111672 revealed that both MET and RIPK2 were expressed in cancer cells while RIPK2 was also expressed in monocytes and neutrophils. After comprehensive analysis, we found that both MET and RIPK2 are related to the prognosis of pancreatic ductal adenocarcinoma and provided some associated clues for clinical application and basic experiment research.

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Du, Min, Xiang Zhou, Xing Fu, Yangzi Zhang, Shuwen Zhang, Jennifer J. Michal, Hongyang Wang, and Zhihua Jiang. "341 Up-regulation of wound healing pathway may trigger adipogenic potentials of intramuscular progenitor cells in Wagyu as compared to Angus cattle." Journal of Animal Science 97, Supplement_3 (December 2019): 95–96. http://dx.doi.org/10.1093/jas/skz258.198.

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Abstract Marbling and muscle growth are significantly different between Angus and Wagyu cattle, but the underlying mechanisms remain unclear. The objective of the present study was to unravel genetic information flows specific to each phenotype. Biopsies of the Biceps femoris muscle were collected from three animals per breed. Intramuscular progenitor cells were isolated from the biopsies and alternative polyadenylation (APA) events were profiled using the WTTS-seq (whole transcriptome termini site sequencing) method. In adipogenic progenitor cells, 271 and 341 differentially expressed (DE) APA sites were identified as upregulated in Angus and Wagyu, respectively (adjusted P < 0.1). Pathway enrichment revealed that cellular wound healing events are unique to Wagyu. For these seven pairs of gene family members (in a broad sense), AKT1, CD47 and CD99, IGFBP3, KIF3A, RIOK1, RUNX1 and THBS1 were upregulated in Angus, while AKT3, CD59 and CD200, IGFBP2 and IGFBP4, KIF3B, RIOK3, RUNX2 and THBS2 were upregulated in Wagyu. There were 313 and 171 upregulated DE-APA sites in satellite cells derived from Angus and Wagyu, respectively (adjusted P < 0.1). Muscle system related pathways were enriched specifically for Angus. The CAPZA1, FAM227B, LDB2 and TTLL4 genes contained at least one DE-APA site that was specifically abundant in Angus or Wagyu. For these six gene family member pairs, ANKRD1, CD82, FBXO17, IGFBP2, PDLIM3 and THBS1 were abundantly expressed in Angus, but ANKRD28, CD9, CD14 and CD164, FBXO33, IGFBP5, PDLIM1 and THBS2 were upregulated in Wagyu. In brief, intramuscular progenitor cells and satellite cells may be characteristically different between Angus and Wagyu. Based on DE-APA events, the myogenesis pathways are enriched in cells from Angus, but the adipogenesis pathways are dominant in cells derived from Wagyu. This research was supported by the USDA-NIFA under Award Numbers 2016-67015-24470/2018-67051-27500 to ZJ and 2015-67015-23219/2016-68006-24634 to MD.

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Zhu, Chengming, Qi Yan, Chenchun Weng, Xinhao Hou, Hui Mao, Dun Liu, Xuezhu Feng, and Shouhong Guang. "Erroneous ribosomal RNAs promote the generation of antisense ribosomal siRNA." Proceedings of the National Academy of Sciences 115, no. 40 (September 17, 2018): 10082–87. http://dx.doi.org/10.1073/pnas.1800974115.

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Ribosome biogenesis is a multistep process, during which mistakes can occur at any step of pre-rRNA processing, modification, and ribosome assembly. Misprocessed rRNAs are usually detected and degraded by surveillance machineries. Recently, we identified a class of antisense ribosomal siRNAs (risiRNAs) that down-regulate pre-rRNAs through the nuclear RNAi pathway. To further understand the biological roles of risiRNAs, we conducted both forward and reverse genetic screens to search for more suppressor of siRNA (susi) mutants. We isolated a number of genes that are broadly conserved from yeast to humans and are involved in pre-rRNA modification and processing. Among them, SUSI-2(ceRRP8) is homologous to human RRP8 and engages in m1A methylation of the 26S rRNA. C27F2.4(ceBUD23) is an m7G-methyltransferase of the 18S rRNA. E02H1.1(ceDIMT1L) is a predicted m6(2)Am6(2)A-methyltransferase of the 18S rRNA. Mutation of these genes led to a deficiency in modification of rRNAs and elicited accumulation of risiRNAs, which further triggered the cytoplasmic-to-nuclear and cytoplasmic-to-nucleolar translocations of the Argonaute protein NRDE-3. The rRNA processing deficiency also resulted in accumulation of risiRNAs. We also isolated SUSI-3(RIOK-1), which is similar to human RIOK1, that cleaves the 20S rRNA to 18S. We further utilized RNAi and CRISPR-Cas9 technologies to perform candidate-based reverse genetic screens and identified additional pre-rRNA processing factors that suppressed risiRNA production. Therefore, we concluded that erroneous rRNAs can trigger risiRNA generation and subsequently, turn on the nuclear RNAi-mediated gene silencing pathway to inhibit pre-rRNA expression, which may provide a quality control mechanism to maintain homeostasis of rRNAs.

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Black, Joshua J., and Arlen W. Johnson. "Release of the ribosome biogenesis factor Bud23 from small subunit precursors in yeast." RNA 28, no. 3 (December 21, 2021): 371–89. http://dx.doi.org/10.1261/rna.079025.121.

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The two subunits of the eukaryotic ribosome are produced through quasi-independent pathways involving the hierarchical actions of numerous trans-acting biogenesis factors and the incorporation of ribosomal proteins. The factors work together to shape the nascent subunits through a series of intermediate states into their functional architectures. One of the earliest intermediates of the small subunit (SSU or 40S) is the SSU processome which is subsequently transformed into the pre-40S intermediate. This transformation is, in part, facilitated by the binding of the methyltransferase Bud23. How Bud23 is released from the resultant pre-40S is not known. The ribosomal proteins Rps0, Rps2, and Rps21, termed the Rps0-cluster proteins, and several biogenesis factors bind the pre-40S around the time that Bud23 is released, suggesting that one or more of these factors could induce Bud23 release. Here, we systematically examined the requirement of these factors for the release of Bud23 from pre-40S particles. We found that the Rps0-cluster proteins are needed but not sufficient for Bud23 release. The atypical kinase/ATPase Rio2 shares a binding site with Bud23 and is thought to be recruited to pre-40S after the Rps0-cluster proteins. Depletion of Rio2 prevented the release of Bud23 from the pre-40S. More importantly, the addition of recombinant Rio2 to pre-40S particles affinity-purified from Rio2-depleted cells was sufficient for Bud23 release in vitro. The ability of Rio2 to displace Bud23 was independent of nucleotide hydrolysis. We propose a novel role for Rio2 in which its binding to the pre-40S actively displaces Bud23 from the pre-40S.

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Waldschmitt, Nadine, Sho Kitamoto, Thomas Secher, Vassiliki Zacharioudaki, Olivier Boulard, Emilie Floquet, Myriam Delacre та ін. "The regenerating family member 3 β instigates IL-17A-mediated neutrophil recruitment downstream of NOD1/2 signalling for controlling colonisation resistance independently of microbiota community structure". Gut 68, № 7 (2 жовтня 2018): 1190–99. http://dx.doi.org/10.1136/gutjnl-2018-316757.

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ObjectiveLoss of the Crohn’s disease predisposing NOD2 gene results in an intestinal microenvironment conducive for colonisation by attaching-and-effacing enteropathogens. However, it remains elusive whether it relies on the intracellular recruitment of the serine-threonine kinase RIPK2 by NOD2, a step that is required for its activation of the transcription factor NF-κB.DesignColonisation resistance was evaluated in wild type and mutant mice, as well as in ex-germ-free (ex-GF) mice which were colonised either with faeces from Ripk2-deficient mice or with bacteria with similar preferences for carbohydrates to those acquired by the pathogen. The severity of the mucosal pathology was quantified at several time points postinfection by using a previously established scoring. The community resilience in response to infection was evaluated by 16S ribosomal RNA gene sequence analysis. The control of pathogen virulence was evaluated by monitoring the secretion of Citrobacter-specific antibody response in the faeces.ResultsPrimary infection was similarly outcompeted in ex-GF Ripk2-deficient and control mice, demonstrating that the susceptibility to infection resulting from RIPK2 deficiency cannot be solely attributed to specific microbiota community structures. In contrast, delayed clearance of Citrobacter rodentium and exacerbated histopathology were preceded by a weakened propensity of intestinal macrophages to afford innate lymphoid cell activation. This tissue protection unexpectedly required the regenerating family member 3β by instigating interleukin (IL) 17A-mediated neutrophil recruitment to the intestine and subsequent phosphorylation of signal transducer and activator of transcription 3.ConclusionsThese results unveil a previously unrecognised mechanism that efficiently protects from colonisation by diarrhoeagenic bacteria early in infection.

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Poudel, Barun, and Prajwal Gurung. "Allergic asthma: RIPK2 takes the lead." Journal of Leukocyte Biology 104, no. 3 (August 14, 2018): 441–43. http://dx.doi.org/10.1002/jlb.3ce0718-293.

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Lucki, Natasha C., Genaro R. Villa, Naja Vergani, Michael J. Bollong, Brittney A. Beyer, Jae Wook Lee, Justin L. Anglin, et al. "A cell type-selective apoptosis-inducing small molecule for the treatment of brain cancer." Proceedings of the National Academy of Sciences 116, no. 13 (March 7, 2019): 6435–40. http://dx.doi.org/10.1073/pnas.1816626116.

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Glioblastoma multiforme (GBM; grade IV astrocytoma) is the most prevalent and aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation, tumor maintenance, metastasis, drug resistance, and recurrence following surgery. Here we report the identification of a small molecule, termed RIPGBM, from a cell-based chemical screen that selectively induces apoptosis in multiple primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of this compound appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an orthotopic intracranial GBM CSC tumor xenograft mouse model, RIPGBM was found to significantly suppress tumor formation in vivo. Our chemical genetics-based approach has identified a drug candidate and a potential drug target that provide an approach to the development of treatments for this devastating disease.

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Jurynec, Michael J., Allen D. Sawitzke, Timothy C. Beals, Michael J. Redd, Jeff Stevens, Brith Otterud, Mark F. Leppert, and David Jonah Grunwald. "A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis." Human Molecular Genetics 27, no. 13 (April 12, 2018): 2383–91. http://dx.doi.org/10.1093/hmg/ddy132.

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Abstract Osteoarthritis (OA) is a common debilitating disease characterized by abnormal remodeling of the cartilage and bone of the articular joint. Ameliorating therapeutics are lacking due to limited understanding of the molecular pathways affecting disease initiation and progression. Notably, although a link between inflammation and overt OA is well established, the role of inflammation as a driver of disease occurrence is highly disputed. We analyzed a family with dominant inheritance of early-onset OA and found that affected individuals harbored a rare variant allele encoding a significant amino acid change (p.Asn104Asp) in the kinase domain of receptor interacting protein kinase 2 (RIPK2), which transduces signals from activated bacterial peptidoglycan sensors through the NF-κB pathway to generate a proinflammatory immune response. Functional analyses of RIPK2 activity in zebrafish embryos indicated that the variant RIPK2104Asp protein is hyperactive in its signaling capacity, with augmented ability to activate the innate immune response and the NF-κB pathway and to promote upregulation of OA-associated genes. Further we show a second allele of RIPK2 linked to an inflammatory disease associated with arthritis also has enhanced activity stimulating the NF-κB pathway. Our studies reveal for the first time the inflammatory response can function as a gatekeeper risk factor for OA.

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Miah, Afjal H., Ian E. D. Smith, Mark Rackham, Alina Mares, Aditya R. Thawani, Rakesh Nagilla, Pamela A. Haile, et al. "Optimization of a Series of RIPK2 PROTACs." Journal of Medicinal Chemistry 64, no. 17 (August 25, 2021): 12978–3003. http://dx.doi.org/10.1021/acs.jmedchem.1c01118.

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Guo, Y., L. A. Dieleman, H. Dooky, H. Joshi, E. Wine, and S. Baksh. "A207 RIPK2 AND AMPK AS EMERGING THERAPEUTIC TARGETS FOR INFLAMMATORY BOWEL DISEASE." Journal of the Canadian Association of Gastroenterology 3, Supplement_1 (February 2020): 79–80. http://dx.doi.org/10.1093/jcag/gwz047.206.

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Abstract Background Persistent inflammation can trigger altered epigenetic, inflammation and bioenergetics states. Inflammatory bowel disease (IBD) is a heterogeneous disease with an abnormal inflammatory state and subsequent metabolic syndrome disorder. Current IBD therapeutics are directed to inhibit inflammatory pathways, such as inflammation of the epithelial cells in the colonic crypts. We hypothesize that in order to achieve mucosal healing and to keep patients in remission we must (i) inhibit inflammatory mediators and (ii) resolve secondary effects of inflammation such a reset of metabolic dysfunction. Aims The aims of this study are to explore correlations between inflammation/metabolic markers and the severity of the disease to uncover emerging new therapeutic players. Methods More than one hundred patients were recruited and underwent colonoscopy. In order to explore how biomarkers change with disease and time, all patients had IBD for more than 10 years or less than 5 years. Those diagnosed with cancer, celiac sprue, or diabetes were excluded. The activity of key metabolic markers (such as AMPK) was tracked using phospho-specific antibodies. Immunohistochemistry and immunoblotting were carried out, as described by Gordon et al., PLOSone 2013. All patients were consented under our IBD ethics protocol (Pro00001523 and Pro00077868). Results Using intestinal biopsies from non-IBD, UC and CD patients, we explored the expression/activation levels of markers of inflammation (such as obligate NOD2 kinase RIPK2) and metabolism (AMPK) in order to gain insight into correlations with clinical severity of the disease. We confirm that the loss in the activity of AMPK occurs with a gain of activity of RIPK2 that drives the inflammatory phenotype of the gut in patients with long-standing IBD (>10 years). (If inflammation is inhibited in a mouse model of IBD, metabolic reset occurs to regain AMPK and promote mucosal healing). However, RIPK2 remains elevated in patients that are currently on IBD therapeutics. Conclusions Therapeutics inhibiting inflammation (RIPK2) and stimulating metabolic (AMPK) drivers of the disease may be a useful combination therapy to completely eliminate inflammation, reset abnormal metabolism and achieve full remission in IBD patients with longstanding disease. Funding Agencies None

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Jorion, Philippe. "Risk2: Measuring the Risk in Value at Risk." Financial Analysts Journal 52, no. 6 (November 1996): 47–56. http://dx.doi.org/10.2469/faj.v52.n6.2039.

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Mangiero, Susan M. "Risk2: Measuring the Risk in Value at Risk." CFA Digest 27, no. 3 (August 1997): 68–69. http://dx.doi.org/10.2469/dig.v27.n3.125.

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Tigno-Aranjuez, Justine T., Pascal Benderitter, Frederik Rombouts, Frederik Deroose, XiaoDong Bai, Benedetta Mattioli, Fabio Cominelli, Theresa T. Pizarro, Jan Hoflack, and Derek W. Abbott. "In VivoInhibition of RIPK2 Kinase Alleviates Inflammatory Disease." Journal of Biological Chemistry 289, no. 43 (September 11, 2014): 29651–64. http://dx.doi.org/10.1074/jbc.m114.591388.

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Maurice, Frédérique, Natacha Pérébaskine, Stéphane Thore, and Sébastien Fribourg. "In vitro dimerization of human RIO2 kinase." RNA Biology 16, no. 11 (August 14, 2019): 1633–42. http://dx.doi.org/10.1080/15476286.2019.1653679.

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Huang, Haina, Melissa Parker, and Katrin Karbstein. "The modifying enzyme Tsr3 establishes the hierarchy of Rio kinase binding in 40S ribosome assembly." RNA 28, no. 4 (January 14, 2022): 568–82. http://dx.doi.org/10.1261/rna.078994.121.

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Ribosome assembly is an intricate process, which in eukaryotes is promoted by a large machinery comprised of over 200 assembly factors (AFs) that enable the modification, folding, and processing of the ribosomal RNA (rRNA) and the binding of the 79 ribosomal proteins. While some early assembly steps occur via parallel pathways, the process overall is highly hierarchical, which allows for the integration of maturation steps with quality control processes that ensure only fully and correctly assembled subunits are released into the translating pool. How exactly this hierarchy is established, in particular given that there are many instances of RNA substrate “handover” from one highly related AF to another, remains to be determined. Here we have investigated the role of Tsr3, which installs a universally conserved modification in the P-site of the small ribosomal subunit late in assembly. Our data demonstrate that Tsr3 separates the binding of the Rio kinases, Rio2 and Rio1, with whom it shares a binding site. By binding after Rio2 dissociation, Tsr3 prevents rebinding of Rio2, promoting forward assembly. After rRNA modification is complete, Tsr3 dissociates, thereby allowing for recruitment of Rio1 into its functional site. Inactive Tsr3 blocks Rio1 function, which can be rescued using mutants that bypass the requirement for Rio1 activity. Finally, yeast strains lacking Tsr3 randomize the binding of the two kinases, leading to the release of immature ribosomes into the translating pool. These data demonstrate a role for Tsr3 and its modification activity in establishing a hierarchy for the function of the Rio kinases.

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Skirboll, Stephen, Natasha Lucki, Genaro Villa, Naja Vergani, Michael Bollong, Brittney Beyer, Jae Wook Lee, et al. "STEM-20. A CANCER STEM CELL-SELECTIVE APOPTOSIS-INDUCING SMALL MOLECULE FOR THE TREATMENT OF GBM." Neuro-Oncology 22, Supplement_2 (November 2020): ii200. http://dx.doi.org/10.1093/neuonc/noaa215.837.

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Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation and maintenance, drug resistance, and recurrence following surgery. New therapeutic strategies for the treatment of GBM have recently focused on targeting CSCs. Here we have used an unbiased large-scale screening approach to identify drug-like small molecules that induce apoptosis in GBM CSCs in a cell type-selective manner. METHODS A luciferase-based survival assay of patient-derived GBM CSC lines was established to perform a large-scale screen of ∼one million drug-like small molecules with the goal of identifying novel compounds that are selectively toxic to chemoresistant GBM CSCs. Compounds found to kill GBM CSC lines as compared to control cell types were further characterized. A caspase activation assay was used to evaluate the mechanism of induced cell death. A xenograft animal model using patient-derived GBM CSCs was employed to test the leading candidate for suppression of in vivo tumor formation. RESULTS We identified a small molecule, termed RIPGBM, from the cell-based chemical screen that induces apoptosis in primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of RIPGBM appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an intracranial GBM xenograft mouse model, RIPGBM was found to significantly suppress tumor formation. CONCLUSIONS Our chemical genetics-based approach has identified a small molecule drug candidate and a potential drug target that selectively targets cancer stem cells and provides an approach for the treatment of GBMs.

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Varin, Thibault, Alexander G. Godfrey, Thierry Masquelin, Christos A. Nicolaou, David A. Evans, and Michal Vieth. "Discovery of selective RIO2 kinase small molecule ligand." Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1854, no. 10 (October 2015): 1630–36. http://dx.doi.org/10.1016/j.bbapap.2015.04.006.

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46

Jurynec, M., A. Sawitzke, T. Beals, B. Otterud, M. Redd, J. Stevens, M. Leppert, and D. Grunwald. "A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis." Osteoarthritis and Cartilage 26 (April 2018): S159. http://dx.doi.org/10.1016/j.joca.2018.02.344.

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Sabnis, Ram W. "Novel Thienopyridines as RIPK2 Inhibitors for Treating Inflammatory Bowel Disease." ACS Medicinal Chemistry Letters 11, no. 12 (November 19, 2020): 2366–67. http://dx.doi.org/10.1021/acsmedchemlett.0c00591.

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Jurynec, Michael J., Allen D. Sawitzke, Timothy C. Beals, Michael J. Redd, Jeff Stevens, Brith Otterud, Mark F. Leppert, and David Jonah Grunwald. "A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis." Human Molecular Genetics 27, no. 13 (May 30, 2018): 2406. http://dx.doi.org/10.1093/hmg/ddy196.

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Weinberg, Florian, Nadine Reischmann, Lisa Fauth, Sanaz Taromi, Justin Mastroianni, Martin Köhler, Sebastian Halbach, et al. "The Atypical Kinase RIOK1 Promotes Tumor Growth and Invasive Behavior." EBioMedicine 20 (June 2017): 79–97. http://dx.doi.org/10.1016/j.ebiom.2017.04.015.

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Wu, Pengcheng, Liping Du, Shengping Hou, Guannan Su, Lu Yang, Jiayue Hu, Jing Deng, et al. "Association of LACC1, CEBPB-PTPN1, RIPK2 and ADO-EGR2 with ocular Behcet’s disease in a Chinese Han population." British Journal of Ophthalmology 102, no. 9 (June 15, 2018): 1308–14. http://dx.doi.org/10.1136/bjophthalmol-2017-311753.

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BackgroundAn Immunochip study recently identified the association of a number of new genetic loci with Behcet’s disease (BD).ObjectiveTo confirm the association between new genetic loci reported in an Immunochip study and BD in a Han Chinese population.MethodsA two-stage association study was carried out in 1238 patients with BD and 1458 healthy controls. Twenty-two candidate single nucleotide polymorphisms (SNPs) were selected for genotyping by iPLEXGold genotyping or TaqMan SNP assays and a meta-analysis was performed for significantly associated markers.ResultsThe results showed that four SNPs (LACC1/rs9316059, CEBPB-PTPN1/rs913678, ADO-EGR2/rs224127 and RIPK2/rs10094579) were associated with BD in an allelic association test (rs9316059 T allele: pc=4.95×10−8, OR=0.687; rs913678 C allele: pc=3.01×10−4, OR=1.297; rs224127 A allele: pc=3.77×10−4, OR=1.274; rs10094579 A allele: pc=6.93×10−4, OR=1.302). For four SNPs tested by meta-analysis, the association with BD was strengthened and all exceeded genome-wide significance (rs9316059: p=2.96×10−16; rs913678: p=2.09×10−16; rs224127: p=5.28×10−13; rs10094579: p=9.21×10−11).ConclusionsOur findings confirmed the association of four loci (LACC1, CEBPB-PTPN1, ADO-EGR2 and RIPK2) in Chinese Han patients with BD.

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