Journal articles: 'Cullin-1'

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Zhou, Yun-Hai, Jiazeng Xia, Wen-Huan Xu, Xiqi Zhu, Xiao-Hong Wu, Dong Hua, and Chungen Xing. "Cullin-1 Promotes Cell Proliferation in Human Breast Cancer and is Related to Diabetes." International Journal of Biological Markers 31, no. 4 (October 2016): 375–81. http://dx.doi.org/10.5301/jbm.5000215.

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Aim Breast carcinoma (BCA) and diabetes mellitus (DM) are two major health problems in women and the general population. Cullin-1 is reported to be an important tumor-related protein involved in cell-cycle progression, signal transduction and transcription. The aim of this work is to investigate the role of Cullin-1 in the development of BCA and to find potential relationships between Cullin-1 and diabetes in BCA patients. Methods To evaluate the function of Cullin-1, we entered 168 patients with primary invasive BCA in this study. Pairs of BCA tissues and adjacent noncancerous tissues from these patients were collected between 2006 and 2008. We used immunohistochemistry to analyze the correlation between Cullin-1 expression and clinicopathological variables and patient survival. In addition, we investigated the role of Cullin-1 in BCA cell proliferation. Results Cullin-1 expression was upregulated in BCA tissues. Enhanced immunoreactivity for Cullin-1 in BCA tissues was inversely correlated with overall survival and disease-free survival, which suggested a poor prognosis in BCA patients. Strong expression of Cullin-1 was more frequently observed in patients with estrogen receptor negativity and HER2 positivity. We also found that Cullin-1 expression was increased in BCA patients with a previous diagnosis of diabetes. Conclusions Our results demonstrate that increased Cullin-1 expression is significantly correlated with poor prognosis in patients with BCA. Cullin-1 might regulate BCA cell proliferation through the ubiquitin-proteasome system. Thus, Cullin-1 might be an important marker and a therapeutic target in BCA.

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Huang, Guochang, Andrew J. Kaufman, Y. Ramanathan, and Bhuvanesh Singh. "SCCRO (DCUN1D1) Promotes Nuclear Translocation and Assembly of the Neddylation E3 Complex." Journal of Biological Chemistry 286, no. 12 (January 19, 2011): 10297–304. http://dx.doi.org/10.1074/jbc.m110.203729.

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SCCRO/DCUN1D1/DCN1 (squamous cell carcinoma-related oncogene/defective in cullin neddylation 1 domain containing 1/defective in cullin neddylation) serves as an accessory E3 in neddylation by binding to cullin and Ubc12 to allow efficient transfer of Nedd8. In this work we show that SCCRO has broader, pleiotropic effects that are essential for cullin neddylation in vivo. Reduced primary nuclear localization of Cul1 accompanying decreased neddylation and proliferation in SCCRO−/− mouse embryonic fibroblasts led us to investigate whether compartmentalization plays a regulatory role. Decreased nuclear localization, neddylation, and defective proliferation in SCCRO−/− mouse embryonic fibroblasts were rescued by transgenic expression of SCCRO. Expression of reciprocal SCCRO and Cul1-binding mutants confirmed the requirement for SCCRO in nuclear translocation and neddylation of cullins in vivo. Nuclear translocation of Cul1 by tagging with a nuclear localization sequence allowed neddylation independent of SCCRO, but at a lower level. We found that in the nucleus, SCCRO enhances recruitment of Ubc12 to Cul1 to promote neddylation. These findings suggest that SCCRO has an essential role in neddylation in vivo involving nuclear localization of neddylation components and recruitment and proper positioning of Ubc12.

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Chadha, Attinder, France Moreau, Shanshan Wang, Antoine Dufour, and Kris Chadee. "Entamoeba histolytica activation of caspase-1 degrades cullin that attenuates NF-κB dependent signaling from macrophages." PLOS Pathogens 17, no. 9 (September 9, 2021): e1009936. http://dx.doi.org/10.1371/journal.ppat.1009936.

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While Entamoeba histolytica (Eh)-induced pro-inflammatory responses are critical in disease pathogenesis, the downstream signaling pathways that subsequently dampens inflammation and the immune response remains unclear. Eh in contact with macrophages suppresses NF-κB signaling while favoring NLRP3-dependent pro-inflammatory cytokine production by an unknown mechanism. Cullin-1 and cullin-5 (cullin-1/5) assembled into a multi-subunit RING E3 ubiquitin ligase complex are substrates for neddylation that regulates the ubiquitination pathway important in NF-κB activity and pro-inflammatory cytokine production. In this study, we showed that upon live Eh contact with human macrophages, cullin-1/4A/4B/5 but not cullin-2/3, were degraded within 10 minutes. Similar degradation of cullin-1/5 were observed from colonic epithelial cells and proximal colonic loops tissues of mice inoculated with live Eh. Degradation of cullin-1/5 was dependent on Eh-induced activation of caspase-1 via the NLRP3 inflammasome. Unlike cullin-4B, the degradation of cullin-4A was partially dependent on caspase-1 and was inhibited with a pan caspase inhibitor. Cullin-1/5 degradation was dependent on Eh cysteine proteinases EhCP-A1 and EhCP-A4, but not EhCP-A5, based on pharmacological inhibition of the cysteine proteinases and EhCP-A5 deficient parasites. siRNA silencing of cullin-1/5 decreased the phosphorylation of pIκ-Bα in response to Eh and LPS stimulation and downregulated NF-κB-dependent TNF-α mRNA expression and TNF-α and MCP-1 pro-inflammatory cytokine production. These results unravel a unique outside-in strategy employed by Eh to attenuate NF-κB-dependent pro-inflammatory responses via NLRP3 activation of caspase-1 that degraded cullin-1/5 from macrophages.

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Murali, Sathish K., Robert Little, Søren B. Poulsen, Mohammed Z. Ferdaus, David H. Ellison, James A. McCormick, and Robert A. Fenton. "Potassium Effects on NCC Are Attenuated during Inhibition of Cullin E3–Ubiquitin Ligases." Cells 11, no. 1 (December 29, 2021): 95. http://dx.doi.org/10.3390/cells11010095.

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The thiazide-sensitive sodium chloride cotransporter (NCC) plays a vital role in maintaining sodium (Na+) and potassium (K+) homeostasis. NCC activity is modulated by with-no-lysine kinases 1 and 4 (WNK1 and WNK4), the abundance of which is controlled by the RING-type E3 ligase Cullin 3 (Cul3) and its substrate adapter Kelch-like protein 3. Dietary K+ intake has an inverse correlation with NCC activity, but the mechanism underlying this phenomenon remains to be fully elucidated. Here, we investigated the involvement of other members of the cullin family in mediating K+ effects on NCC phosphorylation (active form) and abundance. In kidneys from mice fed diets varying in K+ content, there were negative correlations between NCC (phosphorylated and total) and active (neddylated) forms of cullins (Cul1, 3, 4, and 5). High dietary K+ effects on phosphorylated NCC were attenuated in Cul3 mutant mice (CUL3-Het/Δ9). Short-term (30 min) and long-term (24 h) alterations in the extracellular K+ concentration did not affect cullin neddylation levels in ex vivo renal tubules. In the short term, the ability of high extracellular K+ to decrease NCC phosphorylation was preserved in the presence of MLN4924 (pan-cullin inhibitor), but the response to low extracellular K+ was absent. In the long term, MLN4924 attenuated the effects of high extracellular K+ on NCC phosphorylation, and responses to low extracellular K+ were absent. Our data suggest that in addition to Cul3, other cullins are involved in mediating the effects of K+ on NCC phosphorylation and abundance.

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Hammill, Jared T., Daniel C. Scott, Jaeki Min, Michele C. Connelly, Gloria Holbrook, Fangyi Zhu, Amy Matheny, et al. "Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation." Journal of Medicinal Chemistry 61, no. 7 (March 16, 2018): 2680–93. http://dx.doi.org/10.1021/acs.jmedchem.7b01277.

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Makbruri, Makbruri, Isabella Kurnia Liem, Ahmad Aulia Jusuf, and Tantri Hellyanti. "The Dynamics of Cullin-1 Expression in Preeclamptic Placenta and its Association with Pregnancy Termination Time." Open Access Macedonian Journal of Medical Sciences 8, B (May 22, 2020): 210–15. http://dx.doi.org/10.3889/oamjms.2020.3665.

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BACKGROUND: Preeclampsia is a systemic syndrome occurring in 3–5% of pregnancies, caused by disorders of cellular factors resulting in the disruption of trophoblast differentiation and invasion which is important for the placental development and maintaining pregnancy. Cullin-1 is a protein that plays a role in the process of maintaining pregnancy, development, and trophoblast invasion in the placenta. Until now, there have been no studies linking the expression of cullin-1 in preeclamptic patients with the timing of pregnancy termination. AIM: This study analyzed cullin-1 expression in preeclamptic patients and their relationship to the timing of pregnancy termination was carried out. METHODS: Placental samples were taken from preeclampsia patients consisting of three gestational age groups, then immunohistochemical staining was performed to see the dynamics of expression and distribution in each age group of pregnancy and to find out their relationship with the timing of pregnancy termination. RESULTS: Cullin-1 was expressed in syncytiotrophoblasts and cytotrophoblasts. The lowest cullin-1 level was obtained in the very preterm age group, and the highest was found in the moderate preterm gestational age group. There was a significant difference between cullin-1 optical density (OD) expression and termination time of pregnancy, and there was a significant difference (OD) in cullin-1 preeclamptic patients with very preterm gestational age with moderate preterm gestational age. CONCLUSION: Cullin-1 was expressed both in syncytiotrophoblasts and cytotrophoblasts and was associated with the timing of pregnancy termination.

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Driscoll, James, Elias J. Anaissie, and Sajjeev Jagannathan. "Cullin-1 Controls The Clinical and Cellular response to Bortezomib Through NF-Kb Pathway Activation In Myeloma." Blood 122, no. 21 (November 15, 2013): 4445. http://dx.doi.org/10.1182/blood.v122.21.4445.4445.

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The Ubiquitin (Ub)+Proteasome system (UPS) is a highly complex network that maintains cellular homeostasis through the selective turnover of targeted proteins. The proteasome serves as the catalytic core of the UPS to execute the efficient removal of ubiquitin-conjugated proteins. Pharmacologic inhibitors that exploit the pivotal role of the proteasome in cellular metabolism promote tumor cytotoxicity and yield durable clinical responses that have significantly improved survival of patients diagnosed with the invariably fatal plasma cell malignancy multiple myeloma (MM). However, while functional blockade of the proteasome has emerged as a successful anti-cancer strategy, drug resistance inevitably emerges through mechanisms that remain elusive. Since E3 Ub ligases target biologically-relevant proteins for proteasomal degradation and are frequently overexpressed in cancers, we hypothesized that altered E3 Ub ligase expression served as a mechanism of resistance to proteasome inhibitors (PIs). To address the role of individual E3s in myelomagenegesis, gene expression profiles of MM patient samples obtained prior to treatment were analyzed. Results indicated that Cullin-1 was overexpressed in MM patient tumor samples compared to normal or MGUS samples. Cullin-1 is an essential scaffolding component of multiple Skp1-Cullin-1-F-box protein E3 complexes that mediate the ubiquitination of proteins involved in cell cycle progression. Next. bone marrow-derived CD138+ plasma cells were obtained from MM patients that were then treated with the PI bortezomib. Samples were similarly probed to identify differences in E3 expression and to identify features that dictate therapeutic response. Again, Cullin-1 was overexpressed in samples from MM patients that did not respond to bortezomib but Cullin-1 was not overexpressed in samples from those patients that responded to bortezomib. Cullin-1 levels were also higher in bortezomib-resistant myeloma cell lines and drug-resistant cells were re-sensitized to bortezomib after short-hairpin-RNA-mediated Cul-1 knockdown. Cells overexpressing Cullin-1 displayed increased NF-Kappa B activity and a reduced sensitivity to bortezomib-induced apoptosis as demonstrated by staining for annexin-positivity. The effect of Cullin-1 expression level on the sensitivity to bortezomib treatment was determined using MM xenografts in athymic SCID mice. We have used a biologically-supervised, microarray-based approach to identify Cul-1 overexpression in a subset of myeloma patients and correlated expression with clinical resistance to bortezomib. Functional studies demonstrated that Cullin-1 sustains activation of the NF-Kappa B pathway and decreases cellular response to bortezomib in vitro in human cell lines. We conclude that Cullin-1 attenuates bortezomib anti-MM activity by maintaining NF-Kappa B signaling and hence promoting tumor survival. Engineered overexpression or shRNA-mediated inactivation of Cullin-1 modulated the cytotoxic effect of bortezomib to further recapitulate the premise that tumor genomics dictate therapeutic response. Cullin-1 is a novel effector within the UPS that offers promise as an oncologic target either alone or in synergistic combination with proteasome inhibitors. Disclosures: No relevant conflicts of interest to declare.

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Lange, Stephan, Sue Perera, Phildrich Teh, and Ju Chen. "Obscurin and KCTD6 regulate cullin-dependent small ankyrin-1 (sAnk1.5) protein turnover." Molecular Biology of the Cell 23, no. 13 (July 2012): 2490–504. http://dx.doi.org/10.1091/mbc.e12-01-0052.

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Protein turnover through cullin-3 is tightly regulated by posttranslational modifications, the COP9 signalosome, and BTB/POZ-domain proteins that link cullin-3 to specific substrates for ubiquitylation. In this paper, we report how potassium channel tetramerization domain containing 6 (KCTD6) represents a novel substrate adaptor for cullin-3, effectively regulating protein levels of the muscle small ankyrin-1 isoform 5 (sAnk1.5).Binding of sAnk1.5 to KCTD6, and its subsequent turnover is regulated through posttranslational modification by nedd8, ubiquitin, and acetylation of C-terminal lysine residues. The presence of the sAnk1.5 binding partner obscurin, and mutation of lysine residues increased sAnk1.5 protein levels, as did knockdown of KCTD6 in cardiomyocytes. Obscurin knockout muscle displayed reduced sAnk1.5 levels and mislocalization of the sAnk1.5/KCTD6 complex. Scaffolding functions of obscurin may therefore prevent activation of the cullin-mediated protein degradation machinery and ubiquitylation of sAnk1.5 through sequestration of sAnk1.5/KCTD6 at the sarcomeric M-band, away from the Z-disk–associated cullin-3. The interaction of KCTD6 with ankyrin-1 may have implications beyond muscle for hereditary spherocytosis, as KCTD6 is also present in erythrocytes, and erythrocyte ankyrin isoforms contain its mapped minimal binding site.

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Hu, Christine Zhiwen, Jaswinder K. Sethi, and Thilo Hagen. "The Role of the Cullin-5 E3 Ubiquitin Ligase in the Regulation of Insulin Receptor Substrate-1." Biochemistry Research International 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/282648.

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Background. SOCS proteins are known to negatively regulate insulin signaling by inhibiting insulin receptor substrate-1 (IRS1). IRS1 has been reported to be a substrate for ubiquitin-dependent proteasomal degradation. Given that SOCS proteins can function as substrate receptor subunits of Cullin-5 E3 ubiquitin ligases, we examined whether Cullin-5 dependent ubiquitination is involved in the regulation of basal IRS1 protein stability and signal-induced IRS1 degradation.Findings. Our results indicate that basal IRS1 stability varies between cell types. However, the Cullin-5 E3 ligase does not play a major role in mediating IRS1 ubiquitination under basal conditions. Protein kinase C activation triggered pronounced IRS1 destabilization. However, this effect was also independent of the function of Cullin-5 E3 ubiquitin ligases.Conclusions. In conclusion, SOCS proteins do not exert a negative regulatory effect on IRS1 by functioning as substrate receptors for Cullin-5-based E3 ubiquitin ligases both under basal conditions and when IRS1 degradation is induced by protein kinase C activation.

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van Buuren, Nick, Brianne Couturier, Yue Xiong, and Michele Barry. "Ectromelia Virus Encodes a Novel Family of F-Box Proteins That Interact with the SCF Complex." Journal of Virology 82, no. 20 (August 6, 2008): 9917–27. http://dx.doi.org/10.1128/jvi.00953-08.

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ABSTRACT Poxviruses are notorious for encoding multiple proteins that regulate cellular signaling pathways, including the ubiquitin-proteasome system. Bioinformatics indicated that ectromelia virus, the causative agent of lethal mousepox, encoded four proteins, EVM002, EVM005, EVM154, and EVM165, containing putative F-box domains. In contrast to cellular F-box proteins, the ectromelia virus proteins contain C-terminal F-box domains in conjunction with N-terminal ankyrin repeats, a combination that has not been previously reported for cellular proteins. These observations suggested that the ectromelia virus F-box proteins interact with SCF (Skp1, cullin-1, and F-box) ubiquitin ligases. We focused our studies on EVM005, since this protein had only one ortholog in cowpox virus. Using mass spectrometry, we identified cullin-1 as a binding partner for EVM005, and this interaction was confirmed by overexpression of hemagglutinin (HA)-cullin-1. During infection, Flag-EVM005 and HA-cullin-1 colocalized to distinct cellular bodies. Significantly, EVM005 coprecipitated with endogenous Skp1, cullin-1, and Roc1 and associated with conjugated ubiquitin, suggesting that EVM005 interacted with the components of a functional ubiquitin ligase. Interaction of EVM005 with cullin-1 and Skp1 was abolished upon deletion of the F-box, indicating that the F-box played a crucial role in interaction with the SCF complex. Additionally, EVM002 and EVM154 interacted with Skp1 and conjugated ubiquitin, suggesting that ectromelia virus encodes multiple F-box-containing proteins that regulate the SCF complex. Our results indicate that ectromelia virus has evolved multiple proteins that interact with the SCF complex.

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Hammill, Jared T., Deepak Bhasin, Daniel C. Scott, Jaeki Min, Yizhe Chen, Yan Lu, Lei Yang, et al. "Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation." Journal of Medicinal Chemistry 61, no. 7 (March 16, 2018): 2694–706. http://dx.doi.org/10.1021/acs.jmedchem.7b01282.

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Ehrentraut, Stefan F., Valerie F. Curtis, Ruth X. Wang, Bejan J. Saeedi, Heidi Ehrentraut, Joseph C. Onyiah, Caleb J. Kelly, et al. "Perturbation of neddylation-dependent NF-κB responses in the intestinal epithelium drives apoptosis and inhibits resolution of mucosal inflammation." Molecular Biology of the Cell 27, no. 23 (November 15, 2016): 3687–94. http://dx.doi.org/10.1091/mbc.e16-05-0273.

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Recent work has revealed a central role for neddylation (the conjugation of a Nedd8 moiety to Cullin proteins) in the fine-tuning of the NF-κB response (via Cullin-1). In the present study, we investigated the contribution of Cullin-1 neddylation and NF-κB signaling to mucosal inflammatory responses in vitro and in vivo. Initial in vitro studies using cultured intestinal epithelial cells revealed that the neddylation inhibitor MLN4924 prominently induces the deneddylation of Cullin-1. Parallel Western blot, luciferase reporter, and gene target assays identified MLN4924 as a potent inhibitor of intestinal epithelial NF-κB. Subsequent studies revealed that MLN4924 potently induces epithelial apoptosis but only in the presence of additional inflammatory stimuli. In vivo administration of MLN4924 (3 mg/kg per day) in a TNBS-induced colitis model significantly accentuated disease severity. Indeed, MLN4924 resulted in worsened clinical scores and increased mortality early in the inflammatory response. Histologic analysis of the colon revealed that neddylation inhibition results in increased tissue damage and significantly increased mucosal apoptosis as determined by TUNEL and cleaved caspase-3 staining, which was particularly prominent within the epithelium. Extensions of these studies revealed that ongoing inflammation is associated with significant loss of deneddylase-1 (SENP8) expression. These studies reveal that intact Cullin-1 neddylation is central to resolution of acute inflammation.

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Samara, Tjam Diana, Isabella Kurnia Liem, Ani Retno Prijanti, and Andrijono Andrijono. "Cullin 1 is not associated with late-onset preeclampsia." Universa Medicina 38, no. 1 (January 30, 2019): 4. http://dx.doi.org/10.18051/univmed.2019.v38.4-9.

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Background Late-onset preeclampsia (PE) is preeclampsia occurring after 34 weeks of gestational age or later. Cullin 1 (CUL1), a proangiogenic protein, is expressed in the placenta, where an imbalance between proangiogenic and antiangiogenic proteins during gestation can cause disturbance of trophoblast invasion. This defect results in vascular ischemia that may produce preeclampsia. The objective of this study was to determine the correlation between CUL1 as proangiogenic factor and late-onset preeclampsia. Methods This study was of analytical observational cross-sectional design and involved 44 preeclampsia patients with ³34 weeks of gestational age (late-onset PE). The CUL1 level in the subjects’ sera, taken before they gave birth, and in homogenates of their placenta, obtained per vaginam or by cesarean section, were examined by the ELISA technique. Statistical analysis was performed with the Spearman correlation test with significant p value of <0.05. Results Median maternal age was 31 years and median gestational age was 37 weeks. Median serum CUL1 was 41.78 pg/mL and median placental homogenate CUL1 was 32.24 pg per milligram of total placental tissue protein. There was no significant correlation between serum CUL1 level and late-onset preeclampsia (r=-0.281; p=0.065). There was also no significant correlation between placental CUL1 level and late-onset preeclampsia (r=-0.166; p=0.281). Conclusion Serum CUL1 and placental CUL1 were not correlated with late-onset preeclampsia. However, this study indicated that low serum CUL1 tends to prolong gestational age in preeclampsia.

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Mao, Xicheng, Nathan Gluck, Baozhi Chen, Petro Starokadomskyy, Haiying Li, Gabriel N. Maine, and Ezra Burstein. "COMMD1 (Copper Metabolism MURR1 Domain-containing Protein 1) Regulates Cullin RING Ligases by Preventing CAND1 (Cullin-associated Nedd8-dissociated Protein 1) Binding." Journal of Biological Chemistry 286, no. 37 (July 21, 2011): 32355–65. http://dx.doi.org/10.1074/jbc.m111.278408.

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Wu, Kenneth, Robert A. Chong, Qing Yu, Jin Bai, Donald E. Spratt, Kevin Ching, Chan Lee, et al. "Suramin inhibits cullin-RING E3 ubiquitin ligases." Proceedings of the National Academy of Sciences 113, no. 14 (March 21, 2016): E2011—E2018. http://dx.doi.org/10.1073/pnas.1601089113.

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Cullin-RING E3 ubiquitin ligases (CRL) control a myriad of biological processes by directing numerous protein substrates for proteasomal degradation. Key to CRL activity is the recruitment of the E2 ubiquitin-conjugating enzyme Cdc34 through electrostatic interactions between E3′s cullin conserved basic canyon and the acidic C terminus of the E2 enzyme. This report demonstrates that a small-molecule compound, suramin, can inhibit CRL activity by disrupting its ability to recruit Cdc34. Suramin, an antitrypansomal drug that also possesses antitumor activity, was identified here through a fluorescence-based high-throughput screen as an inhibitor of ubiquitination. Suramin was shown to target cullin 1’s conserved basic canyon and to block its binding to Cdc34. Suramin inhibits the activity of a variety of CRL complexes containing cullin 2, 3, and 4A. When introduced into cells, suramin induced accumulation of CRL substrates. These observations help develop a strategy of regulating ubiquitination by targeting an E2–E3 interface through small-molecule modulators.

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Wolfe, Leslie S., Bradford J. Stanley, Chang Liu, William K. Eliason, and Yong Xiong. "Dissection of the HIV Vif Interaction with Human E3 Ubiquitin Ligase." Journal of Virology 84, no. 14 (May 12, 2010): 7135–39. http://dx.doi.org/10.1128/jvi.00031-10.

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ABSTRACT The human immunodeficiency virus type 1 (HIV-1) protein Vif recruits the host E3 ubiquitin ligase, composed of cullin 5 (Cul5), Rbx2, Elongin B, and Elongin C (EloBC), to polyubiquitinate the antiviral protein APOBEC3G. Multiple regions in the C-terminal half of Vif interact with the E3 ligase. We have purified individual regions of Vif and investigated their thermodynamic contributions to the ligase assembly in vitro using isothermal titration calorimetry and fluorescence anisotropy. Our results quantify the high-affinity interactions between the Vif BC box and EloBC and between the Vif zinc finger and Cul5, as well as the modest interaction between the Vif cullin box and Cul5. Our purified Vif constructs also provide direct biochemical evidence that the Vif cullin box, containing the PPLP region, leads to the dimerization of Vif-EloBC complexes but not Cul5-Vif-EloBC complexes.

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Khoury, Joseph, Juan C. Ibla, Andrew S. Neish, and Sean P. Colgan. "Antiinflammatory adaptation to hypoxia through adenosine-mediated cullin-1 deneddylation." Journal of Clinical Investigation 117, no. 3 (March 1, 2007): 703–11. http://dx.doi.org/10.1172/jci30049.

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Hwang, Ji-Won, Kyoeng-Woo Min, Taka-aki Tamura, and Jong-Bok Yoon. "TIP120A associates with unneddylated cullin 1 and regulates its neddylation." FEBS Letters 541, no. 1-3 (April 3, 2003): 102–8. http://dx.doi.org/10.1016/s0014-5793(03)00321-1.

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Burnatowska-Hledin, Maria, P. Zhao, B. Capps, A. Poel, K. Parmelee, C. Mungall, A. Sharangpani, and L. Listenberger. "VACM-1, a cullin gene family member, regulates cellular signaling." American Journal of Physiology-Cell Physiology 279, no. 1 (July 1, 2000): C266—C273. http://dx.doi.org/10.1152/ajpcell.2000.279.1.c266.

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Vasopressin-activated Ca2+-mobilizing (VACM-1) receptor binds arginine vasopressin (AVP) but does not have amino acid sequence homology with the traditional AVP receptors. VACM-1, however, is homologous with a newly discovered cullin family of proteins that has been implicated in the regulation of cell cycle through the ubiquitin-mediated degradation of cyclin-dependent kinase inhibitors. Because cell cycle processes can be regulated by the transmembrane signal transduction systems, the effects of VACM-1 expression on the Ca2+ and cAMP-dependent signaling pathway were examined in a stable cell line expressing VACM-1 in VACM-1 transfected COS-1 cells and in cells cotransfected with VACM-1 and the adenylyl cyclase-linked V2 AVP receptor cDNAs. Expression of the VACM-1 gene reduced basal as well as forskolin- and AVP-stimulated cAMP production. In cells cotransfected with VACM-1 and the V2 receptor, the AVP- and forskolin-induced increases in adenylyl cyclase activity and cAMP production were inhibited. The inhibitory effect of VACM-1 on cAMP production could be reversed by pretreating cells with staurosporin, a protein kinase A (PKA) inhibitor, or by mutating S730A, the PKA-dependent phosphorylation site in the VACM-1 sequence. The protein kinase C specific inhibitor Gö-6983 further enhanced the inhibitory effect of VACM-1 on AVP-stimulated cAMP production. Finally, AVP stimulatedd- myo-inositol 1,4,5-trisphosphate production both in the transiently transfected COS-1 cells and in the stable cell line expressing VACM-1, but not in the control COS-1 and Chinese hamster ovary cells. Our data demonstrate that VACM-1, the first mammalian cullin protein to be characterized, is involved in the regulation of signaling.

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Minor, Marissa M., F. Blaine Hollinger, Adrienne L. McNees, Sung Yun Jung, Antrix Jain, Joseph M. Hyser, Karl-Dimiter Bissig, and Betty L. Slagle. "Hepatitis B Virus HBx Protein Mediates the Degradation of Host Restriction Factors through the Cullin 4 DDB1 E3 Ubiquitin Ligase Complex." Cells 9, no. 4 (March 30, 2020): 834. http://dx.doi.org/10.3390/cells9040834.

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The hepatitis B virus (HBV) regulatory HBx protein is required for infection, and its binding to cellular damaged DNA binding protein 1 (DDB1) is critical for this function. DDB1 is an adaptor protein for the cullin 4A Really Interesting New Gene (RING) E3 ubiquitin ligase (CRL4) complex and functions by binding cellular DDB1 cullin associated factor (DCAF) receptor proteins that recruit substrates for ubiquitination and degradation. We compared the proteins found in the CRL4 complex immunoprecipitated from uninfected versus HBV-infected hepatocytes from human liver chimeric mice for insight into mechanisms by which HBV and the cell interact within the CRL4 complex. Consistent with its role as a viral DCAF, HBx was found in the HBV CRL4 complexes. In tissue culture transfection experiments, we showed that HBx expression led to decreased levels of known restriction factor structural maintenance of chromosomes protein 6 (SMC6) and putative restriction factors stromal interaction molecule 1 (STIM1, zinc finger E-box binding homeobox 2 (ZEB2), and proteasome activator subunit 4 (PSME4). Moreover, silencing of these proteins led to increased HBV replication in the HepG2-sodium taurocholate cotransporting polypeptide (NTCP) infection model. We also identified cellular DCAF receptors in CRL4 complexes from humanized mice. Increasing amounts of HBx did not reveal competitive DCAF binding to cullin4 (CUL4)-DDB1 in plasmid-transfected cells. Our results suggest a model in which HBx benefits virus replication by directly or indirectly degrading multiple cellular restriction factors.

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Canning, Peter, and Alex N. Bullock. "New strategies to inhibit KEAP1 and the Cul3-based E3 ubiquitin ligases." Biochemical Society Transactions 42, no. 1 (January 23, 2014): 103–7. http://dx.doi.org/10.1042/bst20130215.

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E3 ubiquitin ligases that direct substrate proteins to the ubiquitin–proteasome system are promising, though largely unexplored drug targets both because of their function and their remarkable specificity. CRLs [Cullin–RING (really interesting new gene) ligases] are the largest group of E3 ligases and function as modular multisubunit complexes constructed around a Cullin-family scaffold protein. The Cul3-based CRLs uniquely assemble with BTB (broad complex/tramtrack/bric-à-brac) proteins that also homodimerize and perform the role of both the Cullin adapter and the substrate-recognition component of the E3. The most prominent member is the BTB–BACK (BTB and C-terminal Kelch)–Kelch protein KEAP1 (Kelch-like ECH-associated protein 1), a master regulator of the oxidative stress response and a potential drug target for common conditions such as diabetes, Alzheimer's disease and Parkinson's disease. Structural characterization of BTB–Cul3 complexes has revealed a number of critical assembly mechanisms, including the binding of an N-terminal Cullin extension to a bihelical ‘3-box’ at the C-terminus of the BTB domain. Improved understanding of the structure of these complexes should contribute significantly to the effort to develop novel therapeutics targeted to CRL3-regulated pathways.

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Boyer, Laurent, Sara Travaglione, Loredana Falzano, Nils C. Gauthier, Michel R. Popoff, Emmanuel Lemichez, Carla Fiorentini, and Alessia Fabbri. "Rac GTPase Instructs Nuclear Factor-κB Activation by Conveying the SCF Complex and IkBα to the Ruffling Membranes." Molecular Biology of the Cell 15, no. 3 (March 2004): 1124–33. http://dx.doi.org/10.1091/mbc.e03-05-0301.

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Nuclear factor-κB (NF-κB) is a ubiquitously expressed transcription factor that plays a central role in directing a vast range of cellular functions. Its activation is controlled by the Rac GTPase and relies on the coordinated cooperation of the E3–ligase complex SCFβTrCP, composed by Skp-1/Cullin-1, Rbx/Roc1, and the β-TrCP proteins. Recently, Cullin-1 has been reported to form a complex with the activated Rac GTPase. Here, we show that the specific activation of the Rac GTPase, besides directing its own positioning, induces the relocalization of the SCF component Cullin-1 to the ruffling membranes. This occurred only if the ruffles were stimulated by the Rac GTPase and was accompanied by the repositioning to the same intracellular compartment of the SCF protein Skp-1 and the ubiquitin-like molecule Nedd-8. The SCF substrate IkBα was also directed to the ruffling membranes in a Rac-dependent way. The novelty of these findings is in respect to the demonstration that the correct positioning at the ruffling membranes is crucial for the subsequent series of events that leads to IkBα proteasomal degradation and the resultant activation of NF-κB. Consequently, this points to the role of Rac as a docking molecule in NF-κB activation.

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Langer, Simon, Xin Yin, Arturo Diaz, Alex J. Portillo, David E. Gordon, Umu H. Rogers, John M. Marlett, et al. "The E3 Ubiquitin-Protein Ligase Cullin 3 Regulates HIV-1 Transcription." Cells 9, no. 9 (September 1, 2020): 2010. http://dx.doi.org/10.3390/cells9092010.

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The infectious life cycle of the human immunodeficiency virus type 1 (HIV-1) is characterized by an ongoing battle between a compendium of cellular proteins that either promote or oppose viral replication. On the one hand, HIV-1 utilizes dependency factors to support and sustain infection and complete the viral life cycle. On the other hand, both inducible and constitutively expressed host factors mediate efficient and functionally diverse antiviral processes that counteract an infection. To shed light into the complex interplay between HIV-1 and cellular proteins, we previously performed a targeted siRNA screen to identify and characterize novel regulators of viral replication and identified Cullin 3 (Cul3) as a previously undescribed factor that negatively regulates HIV-1 replication. Cul3 is a component of E3-ubiquitin ligase complexes that target substrates for ubiquitin-dependent proteasomal degradation. In the present study, we show that Cul3 is expressed in HIV-1 target cells, such as CD4+ T cells, monocytes, and macrophages and depletion of Cul3 using siRNA or CRISPR/Cas9 increases HIV-1 infection in immortalized cells and primary CD4+ T cells. Conversely, overexpression of Cul3 reduces HIV-1 infection in single replication cycle assays. Importantly, the antiviral effect of Cul3 was mapped to the transcriptional stage of the viral life cycle, an effect which is independent of its role in regulating the G1/S cell cycle transition. Using isogenic viruses that only differ in their promotor region, we find that the NF-κB/NFAT transcription factor binding sites in the LTR are essential for Cul3-dependent regulation of viral gene expression. Although Cul3 effectively suppresses viral gene expression, HIV-1 does not appear to antagonize the antiviral function of Cul3 by targeting it for degradation. Taken together, these results indicate that Cul3 is a negative regulator of HIV-1 transcription which governs productive viral replication in infected cells.

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ZHU, K., X. ZHANG, C. LOU, B. GUO, J. DU, X. WANG, Y. WU, W. KONG, and X. YU. "Peptide Inhibitors of HIV-1 Virus Infection Based on Cullin-5." Chemical Research in Chinese Universities 24, no. 3 (May 2008): 338–43. http://dx.doi.org/10.1016/s1005-9040(08)60071-9.

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Singleton, Kristen D., and Paul E. Wischmeyer. "Glutamine attenuates inflammation and NF-κB activation via Cullin-1 deneddylation." Biochemical and Biophysical Research Communications 373, no. 3 (August 2008): 445–49. http://dx.doi.org/10.1016/j.bbrc.2008.06.057.

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Bowe, Rachael A., Orla T. Cox, Verónica Ayllón, Emilie Tresse, Nollaig C. Healy, Shelley J. Edmunds, Merei Huigsloot, and Rosemary O'Connor. "PDLIM2 regulates transcription factor activity in epithelial-to-mesenchymal transition via the COP9 signalosome." Molecular Biology of the Cell 25, no. 1 (January 2014): 184–95. http://dx.doi.org/10.1091/mbc.e13-06-0306.

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Epithelial cell differentiation and polarized migration associated with epithelial-to-mesenchymal transition (EMT) in cancer requires integration of gene expression with cytoskeletal dynamics. Here we show that the PDZ-LIM domain protein PDLIM2 (Mystique/SLIM), a known cytoskeletal protein and promoter of nuclear nuclear factor κB (NFκB) and signal transducer and activator of transcription (STAT) degradation, regulates transcription factor activity and gene expression through the COP9 signalosome (CSN). Although repressed in certain cancers, PDLIM2 is highly expressed in invasive cancer cells. Here we show that PDLIM2 suppression causes loss of directional migration, inability to polarize the cytoskeleton, and reversal of the EMT phenotype. This is accompanied by altered activity of several transcription factor families, including β-catenin, Ap-1, NFκB, interferon regulatory factors, STATs, JUN, and p53. We also show that PDLIM2 associates with CSN5, and cells with suppressed PDLIM2 exhibit reduced nuclear accumulation and deneddylation activity of the CSN toward the cullin 1 and cullin 3 subunits of cullin-RING ubiquitin ligases. Thus PDLIM2 integrates cytoskeleton signaling with gene expression in epithelial differentiation by controlling the stability of key transcription factors and CSN activity.

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Li, Wei, Leah R. DeBella, Tugba Guven-Ozkan, Rueyling Lin, and Lesilee S. Rose. "An eIF4E-binding protein regulates katanin protein levels in C. elegans embryos." Journal of Cell Biology 187, no. 1 (September 28, 2009): 33–42. http://dx.doi.org/10.1083/jcb.200903003.

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In Caenorhabditis elegans, the MEI-1–katanin microtubule-severing complex is required for meiosis, but must be down-regulated during the transition to embryogenesis to prevent defects in mitosis. A cullin-dependent degradation pathway for MEI-1 protein has been well documented. In this paper, we report that translational repression may also play a role in MEI-1 down-regulation. Reduction of spn-2 function results in spindle orientation defects due to ectopic MEI-1 expression during embryonic mitosis. MEL-26, which is both required for MEI-1 degradation and is itself a target of the cullin degradation pathway, is present at normal levels in spn-2 mutant embryos, suggesting that the degradation pathway is functional. Cloning of spn-2 reveals that it encodes an eIF4E-binding protein that localizes to the cytoplasm and to ribonucleoprotein particles called P granules. SPN-2 binds to the RNA-binding protein OMA-1, which in turn binds to the mei-1 3′ untranslated region. Thus, our results suggest that SPN-2 functions as an eIF4E-binding protein to negatively regulate translation of mei-1.

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Han, Jisoo S., Keiko Hino, Wenzhe Li, Raenier V. Reyes, Cesar P. Canales, Adam M. Miltner, Yasmin Haddadi, et al. "CRL5-dependent regulation of the small GTPases ARL4C and ARF6 controls hippocampal morphogenesis." Proceedings of the National Academy of Sciences 117, no. 37 (September 1, 2020): 23073–84. http://dx.doi.org/10.1073/pnas.2002749117.

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The small GTPase ARL4C participates in the regulation of cell migration, cytoskeletal rearrangements, and vesicular trafficking in epithelial cells. The ARL4C signaling cascade starts by the recruitment of the ARF–GEF cytohesins to the plasma membrane, which, in turn, bind and activate the small GTPase ARF6. However, the role of ARL4C–cytohesin–ARF6 signaling during hippocampal development remains elusive. Here, we report that the E3 ubiquitin ligase Cullin 5/RBX2 (CRL5) controls the stability of ARL4C and its signaling effectors to regulate hippocampal morphogenesis. Both RBX2 knockout and Cullin 5 knockdown cause hippocampal pyramidal neuron mislocalization and development of multiple apical dendrites. We used quantitative mass spectrometry to show that ARL4C, Cytohesin-1/3, and ARF6 accumulate in the RBX2 mutant telencephalon. Furthermore, we show that depletion of ARL4C rescues the phenotypes caused by Cullin 5 knockdown, whereas depletion of CYTH1 or ARF6 exacerbates overmigration. Finally, we show that ARL4C, CYTH1, and ARF6 are necessary for the dendritic outgrowth of pyramidal neurons to the superficial strata of the hippocampus. Overall, we identified CRL5 as a key regulator of hippocampal development and uncovered ARL4C, CYTH1, and ARF6 as CRL5-regulated signaling effectors that control pyramidal neuron migration and dendritogenesis.

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Kim, Sun-Ok, Kyoung Sang Cho, Bo Yeon Kim, and Kyung Ho Lee. "Cullin 1 (CUL1) Promotes Primary Ciliogenesis through the Induction of Ubiquitin-Proteasome-Dependent Dvl2 Degradation." International Journal of Molecular Sciences 22, no. 14 (July 15, 2021): 7572. http://dx.doi.org/10.3390/ijms22147572.

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Primary cilia are nonmotile cellular signal-sensing antenna-like structures composed of microtubule-based structures that distinguish them from motile cilia in structure and function. Primary ciliogenesis is regulated by various cellular signals, such as Wnt, hedgehog (Hh), and platelet-derived growth factor (PDGF). The abnormal regulation of ciliogenesis is closely related to developing various human diseases, including ciliopathies and cancer. This study identified a novel primary ciliogenesis factor Cullin 1 (CUL1), a core component of Skp1-Cullin-F-box (SCF) E3 ubiquitin ligase complex, which regulates the proteolysis of dishevelled 2 (Dvl2) through the ubiquitin-proteasome system. Through immunoprecipitation-tandem mass spectrometry analysis, 176 Dvl2 interacting candidates were identified, of which CUL1 is a novel Dvl2 modulator that induces Dvl2 ubiquitination-dependent degradation. Neddylation-dependent CUL1 activity at the centrosomes was essential for centrosomal Dvl2 degradation and primary ciliogenesis. Therefore, this study provides a new mechanism of Dvl2 degradation by CUL1, which ultimately leads to primary ciliogenesis, and suggest a novel target for primary cilia-related human diseases.

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Gu, Qingyang, G. Tim Bowden, Daniel Normolle, and Yi Sun. "SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1 and IκB-α/NF-κB." Journal of Cell Biology 178, no. 6 (September 10, 2007): 1009–23. http://dx.doi.org/10.1083/jcb.200612067.

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Sensitive to apoptosis gene (SAG)/regulator of cullins-2–Skp1-cullin–F-box protein (SCF) E3 ubiquitin ligase regulates cellular functions through ubiquitination and degradation of protein substrates. We report that, when expressed in mouse epidermis driven by the K14 promoter, SAG inhibited TPA-induced c-Jun levels and activator protein-1 (AP-1) activity in both in vitro primary culture, in vivo transgenic mice, and an AP-1– luciferase reporter mouse model. After AP-1 inactivation, epidermal proliferation induced by 7,12-dimethylbenz(a)-anthracene/12-O-tetradecanoylphorbol-13-acetate at the early stage of carcinogenesis was substantially inhibited. Later stage tumor formation was also substantially inhibited with prolonged latency and reduced frequency of tumor formation. Interestingly, SAG expression increased tumor size, not because of accelerated proliferation, but caused by reduced apoptosis resulting, at least in part, from nuclear factor κB (NF-κB) activation. Thus, SAG, in a manner depending on the availability of F-box proteins, demonstrated early-stage suppression of tumor formation by promoting c-Jun degradation, thereby inhibiting AP-1, and later-stage enhancement of tumor growth, by promoting inhibitor of κBα degradation to activate NF-κB and inhibit apoptosis.

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Cordero-Espinoza, L., and T. Hagen. "Regulation of Cullin-RING ubiquitin ligase 1 by Spliceosome-associated protein 130 (SAP130)." Biology Open 2, no. 8 (June 28, 2013): 838–44. http://dx.doi.org/10.1242/bio.20134374.

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Gao, Daming, Lixin Wan, Hiroyuki Inuzuka, Anders H. Berg, Alan Tseng, Bo Zhai, Shavali Shaik, et al. "Rictor Forms a Complex with Cullin-1 to Promote SGK1 Ubiquitination and Destruction." Molecular Cell 39, no. 5 (September 2010): 797–808. http://dx.doi.org/10.1016/j.molcel.2010.08.016.

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Dubiel, Dawadschargal, Maria Elka Gierisch, Xiaohua Huang, Wolfgang Dubiel, and Michael Naumann. "CAND1-dependent control of cullin 1-RING Ub ligases is essential for adipogenesis." Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1833, no. 5 (May 2013): 1078–84. http://dx.doi.org/10.1016/j.bbamcr.2013.01.005.

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Kominami, Kin-ichiro, Itziar Ochotorena, and Takashi Toda. "Two F-box/WD-repeat proteins Pop1 and Pop2 form hetero- and homo-complexes together with cullin-1 in the fission yeast SCF (Skp1-Cullin-1-F-box) ubiquitin ligase." Genes to Cells 3, no. 11 (November 1998): 721–35. http://dx.doi.org/10.1046/j.1365-2443.1998.00225.x.

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Meister, Thieme, Thieme, Köhler, Schmitt, Valerius, and Braus. "COP9 Signalosome Interaction with UspA/Usp15 Deubiquitinase Controls VeA-Mediated Fungal Multicellular Development." Biomolecules 9, no. 6 (June 18, 2019): 238. http://dx.doi.org/10.3390/biom9060238.

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COP9 signalosome (CSN) and Den1/A deneddylases physically interact and promote multicellular development in fungi. CSN recognizes Skp1/cullin-1/Fbx E3 cullin-RING ligases (CRLs) without substrate and removes their posttranslational Nedd8 modification from the cullin scaffold. This results in CRL complex disassembly and allows Skp1 adaptor/Fbx receptor exchange for altered substrate specificity. We characterized the novel ubiquitin-specific protease UspA of the mold Aspergillus nidulans, which corresponds to CSN-associated human Usp15 and interacts with six CSN subunits. UspA reduces amounts of ubiquitinated proteins during fungal development, and the uspA gene expression is repressed by an intact CSN. UspA is localized in proximity to nuclei and recruits proteins related to nuclear transport and transcriptional processing, suggesting functions in nuclear entry control. UspA accelerates the formation of asexual conidiospores, sexual development, and supports the repression of secondary metabolite clusters as the derivative of benzaldehyde (dba) genes. UspA reduces protein levels of the fungal NF-kappa B-like velvet domain protein VeA, which coordinates differentiation and secondary metabolism. VeA stability depends on the Fbx23 receptor, which is required for light controlled development. Our data suggest that the interplay between CSN deneddylase, UspA deubiquitinase, and SCF-Fbx23 ensures accurate levels of VeA to support fungal development and an appropriate secondary metabolism.

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He, Q., and Y. Liu. "Degradation of the Neurospora circadian clock protein FREQUENCY through the ubiquitin–proteasome pathway." Biochemical Society Transactions 33, no. 5 (October 26, 2005): 953–56. http://dx.doi.org/10.1042/bst0330953.

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Phosphorylation of the Neurospora circadian clock protein FREQUENCY (FRQ) promotes its degradation through the ubiquitin–proteasome pathway. Ubiquitination of FRQ requires FWD-1 (F-box/WD-40 repeat-containing protein-1), which is the substrate-recruiting subunit of an SCF (SKP/Cullin/F-box)-type ubiquitin ligase. In the fwd-1 mutant strains, FRQ degradation is defective, resulting in the accumulation of hyperphosphorylated FRQ and the loss of the circadian rhythmicities. The CSN (COP9 signalosome) promotes the function of SCF complexes in vivo. But in vitro, deneddylation of cullins by CSN inhibits SCF activity. In Neurospora, the disruption of the csn-2 subunit impairs FRQ degradation and compromises the normal circadian functions. These defects are due to the dramatically reduced levels of FWD-1 in the csn-2 mutant, a result of its rapid degradation. Other components of the SCFFWD−1 complex, SKP-1 and CUL-1 are also unstable in the mutant. These results establish important roles for SCFFWD−1 and CSN in the circadian clock of Neurospora and suggest that they are conserved components of the eukaryotic circadian clocks. In addition, these findings resolve the CSN paradox and suggest that the major function of CSN is to maintain the stability of SCF ubiquitin ligases in vivo.

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Kisielnicka, Edyta, Ryuji Minasaki, and Christian R. Eckmann. "MAPK signaling couples SCF-mediated degradation of translational regulators to oocyte meiotic progression." Proceedings of the National Academy of Sciences 115, no. 12 (March 1, 2018): E2772—E2781. http://dx.doi.org/10.1073/pnas.1715439115.

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RNA-binding proteins (RBPs) are important regulators of gene expression programs, especially during gametogenesis. How the abundance of particular RBPs is restricted to defined stages of meiosis remains largely elusive. Here, we report a molecular pathway that subjects two nonrelated but broadly evolutionarily conserved translational regulators (CPB-3/CPEB and GLD-1/STAR) to proteosomal degradation in Caenorhabditis elegans germ cells at the transition from pachytene to diplotene of meiotic prophase. Both RBPs are recognized by the same ubiquitin ligase complex, containing the molecular scaffold Cullin-1 and the tumor suppressor SEL-10/FBXW7 as its substrate recognition subunit. Destabilization of either RBP through this Skp, Cullin, F-box–containing complex (SCF) ubiquitin ligase appears to loosen its negative control over established target mRNAs, and presumably depends on a prior phosphorylation of CPB-3 and GLD-1 by MAPK (MPK-1), whose activity increases in mid- to late pachytene to promote meiotic progression and oocyte differentiation. Thus, we propose that the orchestrated degradation of RBPs via MAPK-signaling cascades during germ cell development may act to synchronize meiotic with sexual differentiation gene expression changes.

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Fu, Ssu-Ju, Meng-Chun Hu, Yi-Jheng Peng, Hsin-Yu Fang, Cheng-Tsung Hsiao, Tsung-Yu Chen, Chung-Jiuan Jeng, and Chih-Yung Tang. "CUL4-DDB1-CRBN E3 Ubiquitin Ligase Regulates Proteostasis of ClC-2 Chloride Channels: Implication for Aldosteronism and Leukodystrophy." Cells 9, no. 6 (May 26, 2020): 1332. http://dx.doi.org/10.3390/cells9061332.

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Voltage-gated ClC-2 channels are essential for chloride homeostasis. Complete knockout of mouse ClC-2 leads to testicular degeneration and neuronal myelin vacuolation. Gain-of-function and loss-of-function mutations in the ClC-2-encoding human CLCN2 gene are linked to the genetic diseases aldosteronism and leukodystrophy, respectively. The protein homeostasis (proteostasis) mechanism of ClC-2 is currently unclear. Here, we aimed to identify the molecular mechanism of endoplasmic reticulum-associated degradation of ClC-2, and to explore the pathophysiological significance of disease-associated anomalous ClC-2 proteostasis. In both heterologous expression system and native neuronal and testicular cells, ClC-2 is subject to significant regulation by cullin-RING E3 ligase-mediated polyubiquitination and proteasomal degradation. The cullin 4 (CUL4)-damage-specific DNA binding protein 1 (DDB1)-cereblon (CRBN) E3 ubiquitin ligase co-exists in the same complex with and promotes the degradation of ClC-2 channels. The CRBN-targeting immunomodulatory drug lenalidomide and the cullin E3 ligase inhibitor MLN4924 promotes and attenuates, respectively, proteasomal degradation of ClC-2. Analyses of disease-related ClC-2 mutants reveal that aldosteronism and leukodystrophy are associated with opposite alterations in ClC-2 proteostasis. Modifying CUL4 E3 ligase activity with lenalidomide and MLN4924 ameliorates disease-associated ClC-2 proteostasis abnormality. Our results highlight the significant role and therapeutic potential of CUL4 E3 ubiquitin ligase in regulating ClC-2 proteostasis.

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Collier-Hyams, Lauren S., Valerie Sloane, Brigid C. Batten, and Andrew S. Neish. "Cutting Edge: Bacterial Modulation of Epithelial Signaling via Changes in Neddylation of Cullin-1." Journal of Immunology 175, no. 7 (September 21, 2005): 4194–98. http://dx.doi.org/10.4049/jimmunol.175.7.4194.

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Ohta, Eri, Masanori Itoh, Masashi Ueda, Yoko Hida, Miao-xing Wang, Miki Hayakawa-Ogura, Shimo Li, et al. "Cullin-4B E3 ubiquitin ligase mediates Apaf-1 ubiquitination to regulate caspase-9 activity." PLOS ONE 14, no. 7 (July 22, 2019): e0219782. http://dx.doi.org/10.1371/journal.pone.0219782.

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Yamoah, K., T. Oashi, A. Sarikas, S. Gazdoiu, R. Osman, and Z. Q. Pan. "Autoinhibitory regulation of SCF-mediated ubiquitination by human cullin 1's C-terminal tail." Proceedings of the National Academy of Sciences 105, no. 34 (August 22, 2008): 12230–35. http://dx.doi.org/10.1073/pnas.0806155105.

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Bosu, Dimple R., Hui Feng, Kyoengwoo Min, Youngjo Kim, Matthew R. Wallenfang, and Edward T. Kipreos. "C. elegans CAND-1 regulates cullin neddylation, cell proliferation and morphogenesis in specific tissues." Developmental Biology 346, no. 1 (October 2010): 113–26. http://dx.doi.org/10.1016/j.ydbio.2010.07.020.

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Techtmann, Stephen, Rodolfo Ghirlando, and Ernest Maynard. "A Hydrodynamic Analysis of the Human Cullin 5 - hIV-1 Vif Ubiquitin Ligase Complex." Biophysical Journal 100, no. 3 (February 2011): 389a. http://dx.doi.org/10.1016/j.bpj.2010.12.2310.

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Moon, Jennifer, Yunde Zhao, Xinhua Dai, Wenjing Zhang, William M. Gray, Enamul Huq, and Mark Estelle. "A New CULLIN 1 Mutant Has Altered Responses to Hormones and Light in Arabidopsis." Plant Physiology 143, no. 2 (December 8, 2006): 684–96. http://dx.doi.org/10.1104/pp.106.091439.

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Sheikh, M. Osman, Yuechi Xu, Hanke van der Wel, Paul Walden, Steven D. Hartson, and Christopher M. West. "Glycosylation of Skp1 Promotes Formation of Skp1–Cullin-1–F-box Protein Complexes inDictyostelium." Molecular & Cellular Proteomics 14, no. 1 (October 23, 2014): 66–80. http://dx.doi.org/10.1074/mcp.m114.044560.

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Gao, Daming, Lixin Wan, and Wenyi Wei. "Phosphorylation of Rictor at Thr1135 impairs the Rictor/Cullin-1 complex to ubiquitinate SGK1." Protein & Cell 1, no. 10 (October 2010): 881–85. http://dx.doi.org/10.1007/s13238-010-0123-x.

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Jang, Sang-Min, Christophe E. Redon, Bhushan L. Thakur, Meriam K. Bahta, and Mirit I. Aladjem. "Regulation of cell cycle drivers by Cullin-RING ubiquitin ligases." Experimental & Molecular Medicine 52, no. 10 (October 2020): 1637–51. http://dx.doi.org/10.1038/s12276-020-00508-4.

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Abstract The last decade has revealed new roles for Cullin-RING ubiquitin ligases (CRLs) in a myriad of cellular processes, including cell cycle progression. In addition to CRL1, also named SCF (SKP1-Cullin 1-F box protein), which has been known for decades as an important factor in the regulation of the cell cycle, it is now evident that all eight CRL family members are involved in the intricate cellular pathways driving cell cycle progression. In this review, we summarize the structure of CRLs and their functions in driving the cell cycle. We focus on how CRLs target key proteins for degradation or otherwise alter their functions to control the progression over the various cell cycle phases leading to cell division. We also summarize how CRLs and the anaphase-promoting complex/cyclosome (APC/C) ligase complex closely cooperate to govern efficient cell cycle progression.

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Schaefer, Henry, and Christopher Rongo. "KEL-8 Is a Substrate Receptor for CUL3-dependent Ubiquitin Ligase That Regulates Synaptic Glutamate Receptor Turnover." Molecular Biology of the Cell 17, no. 3 (March 2006): 1250–60. http://dx.doi.org/10.1091/mbc.e05-08-0794.

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The regulated localization of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors (AMPARs) to synapses is an important component of synaptic signaling and plasticity. Regulated ubiquitination and endocytosis determine the synaptic levels of AMPARs, but it is unclear which factors conduct these processes. To identify genes that regulate AMPAR synaptic abundance, we screened for mutants that accumulate high synaptic levels of the AMPAR subunit GLR-1 in Caenorhabditis elegans. GLR-1 is localized to postsynaptic clusters, and mutants for the BTB-Kelch protein KEL-8 have increased GLR-1 levels at clusters, whereas the levels and localization of other synaptic proteins seem normal. KEL-8 is a neuronal protein and is localized to sites adjacent to GLR-1 postsynaptic clusters along the ventral cord neurites. KEL-8 is required for the ubiquitin-mediated turnover of GLR-1 subunits, and kel-8 mutants show an increased frequency of spontaneous reversals in locomotion, suggesting increased levels of GLR-1 are present at synapses. KEL-8 binds to CUL-3, a Cullin 3 ubiquitin ligase subunit that we also find mediates GLR-1 turnover. Our findings indicate that KEL-8 is a substrate receptor for Cullin 3 ubiquitin ligases that is required for the proteolysis of GLR-1 receptors and suggest a novel postmitotic role in neurons for Kelch/CUL3 ubiquitin ligases.

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Schabla, N. Max, Koushik Mondal, and Patrick C. Swanson. "DCAF1 (VprBP): emerging physiological roles for a unique dual-service E3 ubiquitin ligase substrate receptor." Journal of Molecular Cell Biology 11, no. 9 (December 24, 2018): 725–35. http://dx.doi.org/10.1093/jmcb/mjy085.

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Abstract Cullin-RING ligases (CRLs) comprise a large group of modular eukaryotic E3 ubiquitin ligases. Within this family, the CRL4 ligase (consisting of the Cullin4 [CUL4] scaffold protein, the Rbx1 RING finger domain protein, the DNA damage-binding protein 1 [DDB1], and one of many DDB1-associated substrate receptor proteins) has been intensively studied in recent years due to its involvement in regulating various cellular processes, its role in cancer development and progression, and its subversion by viral accessory proteins. Initially discovered as a target for hijacking by the human immunodeficiency virus accessory protein r, the normal targets and function of the CRL4 substrate receptor protein DDB1–Cul4-associated factor 1 (DCAF1; also known as VprBP) had remained elusive, but newer studies have begun to shed light on these questions. Here, we review recent progress in understanding the diverse physiological roles of this DCAF1 in supporting various general and cell type-specific cellular processes in its context with the CRL4 E3 ligase, as well as another HECT-type E3 ligase with which DCAF1 also associates, called EDD/UBR5. We also discuss emerging questions and areas of future study to uncover the dynamic roles of DCAF1 in normal physiology.

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Nag, Alo, Tanya Bondar, Shalu Shiv, and Pradip Raychaudhuri. "The Xeroderma Pigmentosum Group E Gene Product DDB2 Is a Specific Target of Cullin 4A in Mammalian Cells." Molecular and Cellular Biology 21, no. 20 (October 15, 2001): 6738–47. http://dx.doi.org/10.1128/mcb.21.20.6738-6747.2001.

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ABSTRACT The damaged-DNA binding protein DDB consists of two subunits, DDB1 (127 kDa) and DDB2 (48 kDa). Mutations in the DDB2 subunit have been detected in patients suffering from the repair deficiency disease xeroderma pigmentosum (group E). In addition, recent studies suggested a role for DDB2 in global genomic repair. DDB2 also exhibits transcriptional activity. We showed that expression of DDB1 and DDB2 stimulated the activity of the cell cycle regulatory transcription factor E2F1. Here we show that DDB2 is a cell cycle-regulated protein. It is present at a low level in growth-arrested primary fibroblasts, and after release the level peaks at the G1/S boundary. The cell cycle regulation of DDB2 involves posttranscriptional mechanisms. Moreover, we find that an inhibitor of 26S proteasome increases the level of DDB2, suggesting that it is regulated by the ubiquitin-proteasome pathway. Our previous study indicated that the cullin family protein Cul-4A associates with the DDB2 subunit. Because cullins are involved in the ubiquitin-proteasome pathway, we investigated the role of Cul-4A in regulating DDB2. Here we show that DDB2 is a specific target of Cul-4A. Coexpression of Cul-4A, but not Cul-1 or other highly related cullins, increases the ubiquitination and the decay rate of DDB2. A naturally occurring mutant of DDB2 (2RO), which does not bind Cul-4A, is not affected by coexpression of Cul-4A. Studies presented here identify a specific function of the Cul-4A gene, which is amplified and overexpressed in breast cancers.

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Journal articles on the topic 'Cullin-1'

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