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Journal articles on the topic 'HtrA2/Omi'

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Published: 9 March 2023

Last updated: 10 March 2023

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1

Su, Xiao Juan, Lingyi Huang, Yi Qu, and Dezhi Mu. "Progress in research on the role of Omi/HtrA2 in neurological diseases." Reviews in the Neurosciences 30, no. 3 (April 24, 2019): 279–87. http://dx.doi.org/10.1515/revneuro-2018-0004.

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Abstract Omi/HtrA2 is a serine protease present in the mitochondrial space. When stimulated by external signals, HtrA2 is released into the mitochondrial matrix where it regulates cell death through its interaction with apoptotic and autophagic signaling pathways. Omi/HtrA2 is closely related to the pathogenesis of neurological diseases, such as neurodegeneration and hypoxic ischemic brain damage. Here, we summarize the biological characteristics of Omi/HtrA2 and its role in neurological diseases, which will provide new hints in developing Omi/HtrA2 as a therapeutic target for neurological diseases.

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2

Gupta, Sanjeev, Rajesh Singh, Pinaki Datta, ZhiJia Zhang, Christopher Orr, Zhixian Lu, Garrett DuBois, et al. "The C-terminal Tail of Presenilin Regulates Omi/HtrA2 Protease Activity." Journal of Biological Chemistry 279, no. 44 (August 4, 2004): 45844–54. http://dx.doi.org/10.1074/jbc.m404940200.

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Presenilin mutations are responsible for most cases of autosomal dominant inherited forms of early onset Alzheimer disease. Presenilins play an important role in amyloid β-precursor processing, NOTCH receptor signaling, and apoptosis. However, the molecular mechanisms by which presenilins regulate apoptosis are not fully understood. Here, we report that presenilin-1 (PS1) regulates the proteolytic activity of the serine protease Omi/HtrA2 through direct interaction with its regulatory PDZ domain. We show that a peptide corresponding to the cytoplasmic C-terminal tail of PS1 dramatically increases the proteolytic activity of Omi/HtrA2 toward the inhibitor of apoptosis proteins and β-casein and induces cell death in an Omi/HtrA2-dependent manner. Consistent with these results, ectopic expression of full-length PS1, but not PS1 lacking the C-terminal PDZ binding motif, potentiated Omi/HtrA2-induced cell death. Our results suggest that the C terminus of PS1 is an activation peptide ligand for the PDZ domain of Omi/HtrA2 and may regulate the protease activity of Omi/HtrA2 after its release from the mitochondria during apoptosis. This mechanism of Omi/HtrA2 activation is similar to the mechanism of activation of the related bacterial DegS protease by the outer-membrane porins.

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3

Hur, Kang, Kim, Lee, Kim, Nam, Rhim, and Yoon. "Serine Protease HtrA2/Omi Deficiency Impairs Mitochondrial Homeostasis and Promotes Hepatic Fibrogenesis via Activation of Hepatic Stellate Cells." Cells 8, no. 10 (September 20, 2019): 1119. http://dx.doi.org/10.3390/cells8101119.

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The loss of mitochondrial function impairs intracellular energy production and potentially results in chronic liver disease. Increasing evidence suggests that mitochondrial dysfunction in hepatocytes contributes to the activation of hepatic stellate cells (HSCs), thereby resulting in hepatic fibrogenesis. High-temperature requirement protein A2 (HtrA2/Omi), a mitochondrial serine protease with various functions, is responsible for quality control in mitochondrial homeostasis. However, little information is available regarding its role in mitochondrial damage during the development of liver fibrosis. This study examined whether HtrA2/Omi regulates mitochondrial homeostasis in hepatocyte during the development of hepatic fibrogenesis. In this study, we demonstrated that HtrA2/Omi expression considerably decreased in liver tissues from the CCl4-induced liver fibrotic mice model and from patients with liver cirrhosis. Knockdown of HtrA2/Omi in hepatocytes induced the accumulation of damaged mitochondria and provoked mitochondrial reactive oxygen species (mtROS) stress. We further show that the damaged mtDNA isolated from HtrA2/Omi-deficient hepatocytes as a form of damage-associated molecular patterns can induce HSCs activation. Moreover, we found that motor neuron degeneration 2-mutant mice harboring the missense mutation Ser276Cys in the protease domain of HtrA2/Omi displayed altered mitochondrial morphology and function, which increased oxidative stress and promoted liver fibrosis. Conversely, the overexpression of HtrA2/Omi via hydrodynamics-based gene transfer led to the antifibrotic effects in CCl4-induced liver fibrosis mice model through decreasing collagen accumulation and enhancing anti-oxidative activity by modulating mitochondrial homeostasis in the liver. These results suggest that suppressing HtrA2/Omi expression promotes hepatic fibrogenesis via modulating mtROS generation, and these novel mechanistic insights involving the regulation of mitochondrial homeostasis by HtrA2/Omi may be of importance for developing new therapeutic strategies for hepatic fibrosis.

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4

Wang, Pengfei, Yueyu Hu, Danhua Yao, and Yousheng Li. "Omi/HtrA2 Regulates a Mitochondria-Dependent Apoptotic Pathway in a Murine Model of Septic Encephalopathy." Cellular Physiology and Biochemistry 49, no. 6 (2018): 2163–73. http://dx.doi.org/10.1159/000493819.

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Background/Aims: the pathogenesis of sepsis-associated encephalopathy (SAE) is multifactorial, involving neurotransmitter alterations, inflammatory cytokines, oxidative damage, mitochondrial dysfunction, apoptosis, and other factors. Mitochondria are major producers of reactive oxygen species, resulting in cellular injury. Omi/HtrA2 is a proapoptotic mitochondrial serine protease involved in caspase-dependent cell death; it is translocated from mitochondria to the cytosol after an apoptotic insult. We previously found that UCF-101, a specific inhibitor of Omi/HtrA2, has neuroprotective effects on cerebral oxidative injury and cognitive impairment in septic rats. In this study, the mechanisms and molecular pathways underlying these effects were investigated. Methods: Male Sprague–Dawley rats were subjected to cecal ligation and puncture (CLP) or sham-operated laparotomy and were administered vehicle or UCF-101 (10 µmol/kg). The hippocampus was isolated for subsequent analysis. Omi/HtrA2 expression in the mitochondria or cytosol was evaluated by immunofluorescence or western blotting. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining was utilized to evaluate levels of apoptosis, and western blotting was used to evaluate apoptosis-related proteins, such as cleaved caspase-3, caspase-9, and poly (ADP-ribose) polymerase (PARP). Tight junction expression was assessed by immunofluorescence and western blotting. Mitochondrial function, inflammatory cytokines, and oxidative stress were also assayed. In addition, a wet/dry method was used to evaluate brain edema and Evans blue extravasation was used to evaluate blood–brain barrier (BBB) integrity. Results: After CLP treatment, the hippocampus exhibited a mild increase in Omi/HtrA2 expression; cytosolic Omi/HtrA2 expression increased significantly, whereas mitochondrial Omi/HtrA2 expression was reduced, indicating that CLP-induced oxidative stress resulted in the translocation of Omi/HtrA2 from mitochondria to the cytosol. Hippocampal cleaved caspase-3, caspase-9, and PARP levels were significantly higher in animals treated with CLP than in sham-operated animals, while XIAP expression was lower. Treatment with UCF-101 prevented the mobilization of Omi/HtrA2 from mitochondria to the cytosol, attenuated XIAP degradation, and decreased cleaved caspase-3, caspase-9, and PARP expression as well as apoptosis. UCF-101 also reversed the decreased mitochondrial complex I, II, and III respiration and the reduced ATP caused by CLP. In addition, UCF-101 treatment resulted in a significant improvement in BBB integrity, as demonstrated by increased occludin, claudin-5, and zonula occludens 1 levels and reduced Evans blue extravasation. No significant effects of UCF-101 on brain edema were found. Inflammatory cytokines and oxidative stress were significantly higher in the CLP-treated group than in the sham-operated group. However, the inhibition of Omi/HtrA2 by UCF-101 significantly alleviated these responses. Conclusion: Our data indicated that Omi/ HtrA2 regulates a mitochondria-dependent apoptotic pathway in a murine model of septic encephalopathy. Inhibition of Omi/HtrA2 by UCF-101 leads to neuroprotection by inhibiting the cytosolic translocation of Omi/HtrA2 and antagonizing the caspase-dependent apoptosis pathway. Therapeutic interventions that inhibit Omi/HtrA2 translocation or protease activity may provide a novel method to treat SAE.

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5

Li, Shaoying, Mei Wan, Xu Cao, and Yongsheng Ren. "Expression of AIF and HtrA2/Omi in Small Lymphocytic Lymphoma and Diffuse Large B-Cell Lymphoma." Archives of Pathology & Laboratory Medicine 135, no. 7 (July 1, 2011): 903–8. http://dx.doi.org/10.5858/2010-0003-oar1.1.

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Abstract Context.—The pathogenesis of non-Hodgkin lymphoma may involve deregulation of apoptosis. In response to apoptotic stimuli, several proapoptotic proteins are released into the cytoplasm from the mitochondria, including second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein binding protein with low pI (Smac/DIABLO), apoptosis-inducing factor (AIF), and high temperature requirement protein A2 (HtrA2/Omi). Apoptosis-inducing factor promotes apoptosis through a caspase-independent pathway, while Smac/DIABLO and HtrA2/Omi do so through both caspase-dependent and caspase-independent pathways. Smac/DIABLO was reported to be strongly positive in diffuse large B-cell lymphoma (DLBCL) and virtually absent in small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL). Little is known about the expression of AIF and HtrA2/Omi in lymphomas. Objective.—To evaluate the expression of AIF and HtrA2/Omi in SLL and DLBCL. Design.—Twenty-three DLBCLs, 20 SLLs/CLLs, and 10 benign lymph nodes were evaluated for AIF and HtrA2/Omi expression by immunohistochemical staining. Results.—Apoptosis-inducing factor was strongly and diffusely expressed in 19 of 23 (83%) cases of DLBCL with comparable expression pattern between germinal center–like and non-germinal center–like subgroups. Apoptosis-inducing factor was weakly positive in 15 of 20 (75%) cases of SLL/CLL with increased intensity in pseudofollicles. In contrast, HtrA2/Omi was weakly expressed in SLL/CLL (17 of 20; 85%) and DLBCL (18 of 23; 78%). Conclusions.—The different expression level and pattern of AIF and HtrA2/Omi in SLL/CLL and DLBCL may suggest different apoptotic mechanisms involved in the pathogenesis and prognosis of these diseases. HtrA2/Omi does not appear to be a major player in the regulation of apoptosis of DLBCL and SLL/CLL.

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6

Winkler, Jeannine, Margaret Rand, Markus Schmugge, and Oliver Speer. "Omi/HtrA2 and XIAP are components of platelet apoptosis signalling." Thrombosis and Haemostasis 109, no. 03 (2013): 532–39. http://dx.doi.org/10.1160/th12-06-0404.

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SummaryAlthough platelets possess the hallmarks of apoptosis such as activation of caspases, cytochrome c release and depolarisation of the mitochondrial transmembrane potential (ΔΨm), their entire apoptotic-signalling pathway is not totally understood. Therefore we studied the expression of various apoptotic proteins and found that platelets contain the pro-apoptotic proteins Omi/HtrA2 and Smac/Diablo, as well as their target the X-linked inhibitor of apoptosis XIAP. Omi/HtrA2 and Smac/Diablo were released from mitochondria into the platelet cytosol together with cytochrome c after induction of apoptosis by the Ca2+ ionophore A23187 or the BH3 mimetic ABT-737, and to a lesser extent, after platelet stimulation with collagen and thrombin. Inhibition of Omi/HtrA2 led to decreased levels of activated caspase-3/7 and caspase-9, but did not abolish loss of ΔΨm or prevent release of Omi/HtrA2 from mitochondria. These results indicate that platelets have a functional intrinsic apoptotic-signalling pathway including the pro-apoptotic protease Omi/HtrA2 and its target protein XIAP.

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7

Senn, Joseph, Vilmos Csizmadia, Paul Hales, Larry Dick, and Vivek J. Kadambi. "Proteasome Inhibitors Do Not Inhibit the Serine Protease HtrA2/Omi." Blood 120, no. 21 (November 16, 2012): 5023. http://dx.doi.org/10.1182/blood.v120.21.5023.5023.

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Abstract Abstract 5023 Based on unprecedented efficacy, the proteasome inhibitor (PI) bortezomib has become the cornerstone of multiple myeloma treatment. Nevertheless, in a subset of patients bortezomib causes painful peripheral neuropathy and this side effect can limit its potential benefit for those patients. Although the mechanism of bortezomib associated neuropathy is unknown, we have previously suggested that it is related to the mechanism of action (Csizmadia at. al. Vet Pathol 2010; 47:358–367.). Recently Arastu-Kapur et al. (Clin Cancer Res 2011;17:2734–2743.) have reported that the serine protease HtrA2/Omi was inhibited by bortezomib (a peptide boronate proteasome inhibitor) and not by carfilzomib (an epoxyketone proteasome inhibitor). Further, since HtrA2/Omi is involved in neuronal survival (Martins et al. Mol Cell Biol 2004; 24: 9848–9862.) they suggested that this off target inhibition by bortezomib could be the mechanism underlying bortezomib associated peripheral neuropathy. To confirm and extend these published results, we investigated the effects of these two PIs on HtrA2/Omi activity in recombinant enzyme assays, in SH-SY5Y neuroblastoma-, and wild type and HtrA2/Omi double negative mouse embryonic fibroblast cells (MEF). In contrast to the results of Arastu-Kapur et al., our results clearly demonstrated that neither bortezomib nor carfilzomib inhibits HtrA2/Omi in recombinant enzyme assays at concentrations up to 100μM. As a positive control we used Ucf-101 an HtrA2/Omi specific inhibitor (Cilenti et al. J Biol Chem 2003; 278:11489–11494.) which in our assay behaved in a manner consistent with the published literature. Similarly, in MEF cells, only Ucf-101 prevented the degradation of validated HtrA2/Omi substrates eIF4G1 and UCH-L1, while neither bortezomib nor carfilzomib prevented the degradation of these two substrates. In conclusion, we have assessed the protease activity of HtrA2/Omi both in vitro with purified enzyme and in cultured cells and we find that neither PI inhibits this protease. Therefore we think it is unlikely that PI associated peripheral neuropathy is caused by off target inhibition of HtrA2/Omi. Further research is needed to understand the side effects of PIs. Disclosures: Senn: Millennium Pharmaceuticals, Inc.: Employment. Csizmadia:Millennium Pharmaceuticals, Inc.: Employment. Hales:Millennium Pharmaceuticals, Inc.: Employment. Dick:Millennium Pharmaceuticals, Inc.: Employment. Kadambi:Millennium Pharmaceuticals, Inc.: Employment.

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Balakrishnan, Meenakshi P., Lucia Cilenti, Zineb Mashak, Paiyal Popat, Emad S. Alnemri, and Antonis S. Zervos. "THAP5 is a human cardiac-specific inhibitor of cell cycle that is cleaved by the proapoptotic Omi/HtrA2 protease during cell death." American Journal of Physiology-Heart and Circulatory Physiology 297, no. 2 (August 2009): H643—H653. http://dx.doi.org/10.1152/ajpheart.00234.2009.

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Omi/HtrA2 is a mitochondrial serine protease that has a dual function: while confined in the mitochondria, it promotes cell survival, but when released into the cytoplasm, it participates in caspase-dependent as well as caspase-independent cell death. To investigate the mechanism of Omi/HtrA2's function, we set out to isolate and characterize novel substrates for this protease. We have identified Thanatos-associated protein 5 (THAP5) as a specific interactor and substrate of Omi/HtrA2 in cells undergoing apoptosis. This protein is an uncharacterized member of the THAP family of proteins. THAP5 has a unique pattern of expression and is found predominantly in the human heart, although a very low expression is also seen in the human brain and muscle. THAP5 protein is localized in the nucleus and, when ectopically expressed, induces cell cycle arrest. During apoptosis, THAP5 protein is degraded, and this process can be blocked using a specific Omi/HtrA2 inhibitor, leading to reduced cell death. In patients with coronary artery disease, THAP5 protein levels substantially decrease in the myocardial infarction area, suggesting a potential role of this protein in human heart disease. This work identifies human THAP5 as a cardiac-specific nuclear protein that controls cell cycle progression. Furthermore, during apoptosis, THAP5 is cleaved and removed by the proapoptotic Omi/HtrA2 protease. Taken together, we provide evidence to support that THAP5 and its regulation by Omi/HtrA2 provide a new link between cell cycle control and apoptosis in cardiomyocytes.

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9

Zhang, Yong, Wen-Bin Dong, Li Qing-Ping, Chun-Liang Deng, Tao Xiong, Xiao-Ping Lei, and Lin Guo. "The role of Omi/HtrA2 protease in neonatal postasphyxial serum-induced apoptosis in human kidney proximal tubule cells." Archives of Biological Sciences 64, no. 2 (2012): 435–44. http://dx.doi.org/10.2298/abs1202435z.

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Omi/HtrA2, a proapoptotic mitochondrial serine protease, is involved in both caspase-dependent and caspaseindependent apoptosis. A growing body of evidence indicates that Omi/HtrA2 plays an important role in the pathogenesis of a variety of ischemia-reperfusion (I/R) injuries. However, the role of Omi/HtrA2 in renal injuries that occur in neonates with asphyxia remains unknown. The present study was designed to investigate whether Omi/HtrA2 plays an important role in the types of renal injuries that are induced by neonatal postasphyxial serum. Human renal proximal tubular cell line (HK-2) cells were used as targets. A 20% serum taken from neonates one day after asphyxia was applied to target cells as an attacking factor. We initially included control and postasphyxial serum-attacked groups and later included a ucf-101 group in the study. In the postasphyxial serum-treated group, cytosolic Omi/HtrA2 and caspase-3 expression in HK-2 cells was significantly higher than in the control group. Moreover, the concentration of cytosolic caspase-3 was found to be markedly decreased in HK-2 cells in the ucf-101 group. Our results suggest both that postasphyxial serum has a potent apoptosis-inducing effect on HK-2 cells and that this effect can be partially blocked by ucf-101. Taken together, our results demonstrate for the first time that postasphyxial serum from neonates results in Omi/HtrA2 translocation from the mitochondria to the cytosol, where it promotes HK-2 cell apoptosis via a protease activity-dependent, caspase-mediated pathway.

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Zhang, Yong, Wen-Bin Dong, Qing-Ping Li, Chun-Liang Deng, Tao Xiong, Xiao-Ping Lei, and Lin Guo. "The role of Omi/HtrA2 protease in neonatal postasphyxial serum-induced apoptosis in human kidney proximal tubule cells." Archives of Biological Sciences 64, no. 4 (2012): 1505–14. http://dx.doi.org/10.2298/abs1204505z.

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Omi/HtrA2, a proapoptotic mitochondrial serine protease, is involved in both caspase-dependent and caspaseindependent apoptosis. A growing body of evidence indicates that Omi/HtrA2 plays an important role in the pathogenesis of a variety of ischemia/reperfusion (I/R) injuries. However, the role of Omi/HtrA2 in the renal injuries that occur in neonates with asphyxia remains unknown. The present study was designed to investigate whether Omi/HtrA2 plays an important role in the types of renal injuries that are induced by neonatal postasphyxial serum. Human renal proximal tubular cell line (HK-2) cells were used as targets. A 20% serum taken from neonates one day after asphyxia was applied to the target cells as an attacking factor. We initially included control and postasphyxial-serum-attacked groups and later included a ucf-101 group in the study. In the postasphyxial-serum-treated group, cytosolic Omi/HtrA2 and caspase-3 expression in the HK-2 cells was significantly higher than in the control group. Moreover, the concentration of cytosolic caspase-3 was found to be markedly decreased in HK-2 cells in the ucf-101 group. Our results suggest both that postasphyxial serum has a potent apoptosis-inducing effect on HK-2 cells and that this effect can be partially blocked by ucf-101. Taken together, our results demonstrate for the first time that postasphyxial serum from neonates results in Omi/HtrA2 translocation from the mitochondria to the cytosol, where it promotes HK-2 cell apoptosis via a protease activity-dependent, caspasemediated pathway.

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Yamauchi, Shota, Yan Yan Hou, Alvin Kunyao Guo, Hiroaki Hirata, Wataru Nakajima, Ai Kia Yip, Cheng-han Yu, et al. "p53-mediated activation of the mitochondrial protease HtrA2/Omi prevents cell invasion." Journal of Cell Biology 204, no. 7 (March 24, 2014): 1191–207. http://dx.doi.org/10.1083/jcb.201309107.

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Oncogenic Ras induces cell transformation and promotes an invasive phenotype. The tumor suppressor p53 has a suppressive role in Ras-driven invasion. However, its mechanism remains poorly understood. Here we show that p53 induces activation of the mitochondrial protease high-temperature requirement A2 (HtrA2; also known as Omi) and prevents Ras-driven invasion by modulating the actin cytoskeleton. Oncogenic Ras increases accumulation of p53 in the cytoplasm, which promotes the translocation of p38 mitogen-activated protein kinase (MAPK) into mitochondria and induces phosphorylation of HtrA2/Omi. Concurrently, oncogenic Ras also induces mitochondrial fragmentation, irrespective of p53 expression, causing the release of HtrA2/Omi from mitochondria into the cytosol. Phosphorylated HtrA2/Omi therefore cleaves β-actin and decreases the amount of filamentous actin (F-actin) in the cytosol. This ultimately down-regulates p130 Crk-associated substrate (p130Cas)-mediated lamellipodia formation, countering the invasive phenotype initiated by oncogenic Ras. Our novel findings provide insights into the mechanism by which p53 prevents the malignant progression of transformed cells.

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Li, Haijun, Fucheng He, Xin Zhao, Yuan Zhang, Xi Chu, Chunlan Hua, Yunhui Qu, Yu Duan, and Liang Ming. "YAP Inhibits the Apoptosis and Migration of Human Rectal Cancer Cells via Suppression of JNK-Drp1-Mitochondrial Fission-HtrA2/Omi Pathways." Cellular Physiology and Biochemistry 44, no. 5 (2017): 2073–89. http://dx.doi.org/10.1159/000485946.

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Background/Aims: The Hippo-Yap pathway is associated with tumor development and progression. However, little evidence is available concerning its role in cancer cell apoptosis and migration via mitochondrial homeostasis. Here, we identify mitochondrial fission as a regulator of the Hippo–Yap pathway in human rectal cancer tumorigenesis and metastasis. Methods: In this study, we performed loss-of function assays concerning Yap in RCC via shRNA. Cellular viability and apoptosis were measured via MTT, the TUNEL assay and trypan blue staining. Mitochondrial function was assessed via JC1 staining, the mPTP opening assay, mitochondrial respiratory function analysis, electron microscopy and immunofluorescence analysis of HtrA2/Omi. Mitophagy and mitochondrial fission were assessed via western blots and immunofluorescence. Cell migration was evaluated via the Transwell assay, wound-healing assay and immunofluorescence analysis of F-actin. The interaction between JNK and Yap was detected via co-immunoprecipitation and Yap recombinant mutagenic plasmid transfection. Western blots were used to analyze signaling pathways in conjunction with JNK inhibitors or HtrA2/Omi siRNA. Results: Yap is upregulated in human rectal cancer cells, where its expression correlates positively with cell survival and migration. Functional studies established that silencing of Yap drove JNK phosphorylation, which induced Drp1 activation and translocation to the surface of mitochondria, initiating mitochondrial fission. Excessive mitochondrial fission mediated HtrA2/Omi leakage from the mitochondria into the cytoplasm, where HtrA2/Omi triggered cellular apoptosis via the mitochondrial apoptosis pathway. Moreover, released HtrA2/Omi also phosphorylated cofilin and inhibited cofilin-mediated F-actin polymerization. F-actin collapse perturbed lamellipodia formation and therefore impaired cellular migration and invasion. Conclusion: Collectively, our results demonstrate that Hippo-Yap can serve as a tumor promoter in human rectal cancer and acts by restricting JNK/Drp1/mitochondrial fission/ HtrA2/Omi, with potential implications for new approaches to human rectal cancer therapy.

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Martins, L. Miguel, Alastair Morrison, Kristina Klupsch, Valentina Fedele, Nicoleta Moisoi, Peter Teismann, Alejandro Abuin, et al. "Neuroprotective Role of the Reaper-Related Serine Protease HtrA2/Omi Revealed by Targeted Deletion in Mice." Molecular and Cellular Biology 24, no. 22 (November 15, 2004): 9848–62. http://dx.doi.org/10.1128/mcb.24.22.9848-9862.2004.

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ABSTRACT The serine protease HtrA2/Omi is released from the mitochondrial intermembrane space following apoptotic stimuli. Once in the cytosol, HtrA2/Omi has been implicated in promoting cell death by binding to inhibitor of apoptosis proteins (IAPs) via its amino-terminal Reaper-related motif, thus inducing caspase activity, and also in mediating caspase-independent death through its own protease activity. We report here the phenotype of mice entirely lacking expression of HtrA2/Omi due to targeted deletion of its gene, Prss25. These animals, or cells derived from them, show no evidence of reduced rates of cell death but on the contrary suffer loss of a population of neurons in the striatum, resulting in a neurodegenerative disorder with a parkinsonian phenotype that leads to death of the mice around 30 days after birth. The phenotype of these mice suggests that it is the protease function of this protein and not its IAP binding motif that is critical. This conclusion is reinforced by the finding that simultaneous deletion of the other major IAP binding protein, Smac/DIABLO, does not obviously alter the phenotype of HtrA2/Omi knockout mice or cells derived from them. Mammalian HtrA2/Omi is therefore likely to function in vivo in a manner similar to that of its bacterial homologues DegS and DegP, which are involved in protection against cell stress, and not like the proapoptotic Reaper family proteins in Drosophila melanogaster.

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Liu, Ming-Jie, Meng-Lu Liu, Yan-Fei Shen, Jin-Man Kim, Byung-Ho Lee, Youn-Sik Lee, and Seong-Tshool Hong. "Transgenic mice with neuron-specific overexpression of HtrA2/Omi suggest a neuroprotective role for HtrA2/Omi." Biochemical and Biophysical Research Communications 362, no. 2 (October 2007): 295–300. http://dx.doi.org/10.1016/j.bbrc.2007.07.118.

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Ding, Youming, Bin Wang, Xiaoyan Chen, Yu Zhou, and Jianhui Ge. "Staurosporine suppresses survival of HepG2 cancer cells through Omi/HtrA2-mediated inhibition of PI3K/Akt signaling pathway." Tumor Biology 39, no. 3 (March 2017): 101042831769431. http://dx.doi.org/10.1177/1010428317694317.

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Staurosporine, which is an inhibitor of a broad spectrum of protein kinases, has shown cytotoxicity on several human cancer cells. However, the underlying mechanism is not well understood. In this study, we examined whether and how this compound has an inhibitory action on phosphatidylinositol 3-kinase (PI3K)/Akt pathway in vitro using HepG2 human hepatocellular carcinoma cell line. Cell viability and apoptosis were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and terminal deoxyribonucleotidyl transferase–mediated dUTP-digoxigenin nick end labeling (TUNEL) assay, respectively. Glutathione S-transferase (GST) pull-down assay and co-immunoprecipitation were performed to detect protein–protein interactions. Small interfering RNA (siRNA) was used to silence the expression of targeted protein. We found that staurosporine significantly decreased cell viability and increased cell apoptosis in a concentration- and time-dependent manner in HepG2 cancer cells, along with the decreased expressions of PDK1 protein and Akt phosphorylation. Staurosporine was also found to enhance Omi/HtrA2 release from mitochondria. Furthermore, Omi/HtrA2 directly bound to PDK1. Pharmacological and genetic inhibition of Omi/HtrA2 restored protein levels of PDK1 and protected HepG2 cancer cells from staurosporine-induced cell death. In addition, staurosporine was found to activate autophagy. However, inhibition of autophagy exacerbated cell death under concomitant treatment with staurosporine. Taken together, our results indicate that staurosporine induced cytotoxicity response by inhibiting PI3K/Akt signaling pathway through Omi/HtrA2-mediated PDK1 degradation, and the process provides a novel mechanism by which staurosporine produces its therapeutic effects.

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Vande Walle, Lieselotte, Petra Van Damme, Mohamed Lamkanfi, Xavier Saelens, Joël Vandekerckhove, Kris Gevaert, and Peter Vandenabeele. "Proteome-wide Identification of HtrA2/Omi Substrates." Journal of Proteome Research 6, no. 3 (March 2007): 1006–15. http://dx.doi.org/10.1021/pr060510d.

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17

Vaux, David L., and John Silke. "HtrA2/Omi, a Sheep in Wolf's Clothing." Cell 115, no. 3 (October 2003): 251–53. http://dx.doi.org/10.1016/s0092-8674(03)00851-1.

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18

Hong, Seung-Keun, Mee-Kyung Cha, and Il-Han Kim. "Specific protein interaction of human Pag with Omi/HtrA2 and the activation of the protease activity of Omi/HtrA2." Free Radical Biology and Medicine 40, no. 2 (January 2006): 275–84. http://dx.doi.org/10.1016/j.freeradbiomed.2005.08.029.

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19

Kim, Jinu, Dong Sun Kim, Mae Ja Park, Hee-Jung Cho, Antonis S. Zervos, Joseph V. Bonventre, and Kwon Moo Park. "Omi/HtrA2 protease is associated with tubular cell apoptosis and fibrosis induced by unilateral ureteral obstruction." American Journal of Physiology-Renal Physiology 298, no. 6 (June 2010): F1332—F1340. http://dx.doi.org/10.1152/ajprenal.00737.2009.

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Kidney fibrosis, a typical characteristic of chronic renal disease, is associated with tubular epithelial cell apoptosis. The results of our recent studies have shown that Omi/HtrA2 (Omi), a proapoptotic mitochondrial serine protease, performs a crucial function in renal tubular epithelial apoptotic cell death in animal models of acute kidney injury, including cisplatin toxicity and ischemia-reperfusion insult. However, the role of Omi in tubulointerstitial disease-associated fibrosis in the kidney remains to be clearly defined. We evaluated the potential function and molecular mechanism of Omi in ureteral obstruction-induced kidney epithelial cell apoptosis and fibrosis. The mice were subjected to unilateral ureteral obstruction (UUO) via the ligation of the left ureter near the renal pelvis. UUO increased the protein level of Omi in the cytosolic fraction of the kidney, with a concomitant reduction in the mitochondrial fraction. UUO reduced the X-linked inhibitor of apoptosis protein (XIAP), a substrate of Omi, and pro-caspase-3, whereas it increased cleaved poly(ADP-ribose) polymerase (cleaved PARP) and the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells. When mice were treated with ucf-101, an inhibitor of the proteolytic activity of Omi (6.19 μg/day ip), on a daily basis beginning 2 days before UUO and continuing until the end of the experiment, the Omi inhibitor protected XIAP cleavage after UUO and reduced the increment of PARP cleavage and the numbers of TUNEL-positive cells. Furthermore, the Omi inhibitor significantly attenuated UUO-induced increases in fibrotic characteristics in the kidney, including the atrophy and dilation of tubules, expansion of the interstitium, and increases in the expression of collagens, α-smooth muscle actin, and fibronectin. In conclusion, Omi/HtrA2 is associated with apoptotic signaling pathways in tubular epithelial cells activated by unilateral ureteral obstruction, thereby resulting in kidney fibrosis.

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Vande Walle, L., M. Lamkanfi, and P. Vandenabeele. "The mitochondrial serine protease HtrA2/Omi: an overview." Cell Death & Differentiation 15, no. 3 (January 4, 2008): 453–60. http://dx.doi.org/10.1038/sj.cdd.4402291.

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Ross, Owen A., Alexandra I. Soto, Carles Vilariño-Güell, Michael G. Heckman, Nancy N. Diehl, Mary M. Hulihan, Jan O. Aasly, et al. "Genetic variation of Omi/HtrA2 and Parkinson's disease." Parkinsonism & Related Disorders 14, no. 7 (November 2008): 539–43. http://dx.doi.org/10.1016/j.parkreldis.2008.08.003.

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Huttunen, Henri J., Suzanne Y. Guénette, Camilla Peach, Christopher Greco, Weiming Xia, Doo Yeon Kim, Cory Barren, Rudolph E. Tanzi, and Dora M. Kovacs. "HtrA2 Regulates β-Amyloid Precursor Protein (APP) Metabolism through Endoplasmic Reticulum-associated Degradation." Journal of Biological Chemistry 282, no. 38 (August 6, 2007): 28285–95. http://dx.doi.org/10.1074/jbc.m702951200.

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Alzheimer disease-associated β-amyloid peptide is generated from its precursor protein APP. By using the yeast two-hybrid assay, here we identified HtrA2/Omi, a stress-responsive chaperone-protease as a protein binding to the N-terminal cysteinerich region of APP. HtrA2 coimmunoprecipitates exclusively with immature APP from cell lysates as well as mouse brain extracts and degrades APP in vitro. A subpopulation of HtrA2 localizes to the cytosolic side of the endoplasmic reticulum (ER) membrane where it contributes to ER-associated degradation of APP together with the proteasome. Inhibition of the proteasome results in accumulation of retrotranslocated forms of APP and increased association of APP with HtrA2 and Derlin-1 in microsomal membranes. In cells lacking HtrA2, APP holoprotein is stabilized and accumulates in the early secretory pathway correlating with elevated levels of APP C-terminal fragments and increased Aβ secretion. Inhibition of ER-associated degradation (either HtrA2 or proteasome) promotes binding of APP to the COPII protein Sec23 suggesting enhanced trafficking of APP out of the ER. Based on these results we suggest a novel function for HtrA2 as a regulator of APP metabolism through ER-associated degradation.

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Cilenti, Lucia, George A. Kyriazis, Mangala M. Soundarapandian, Valerie Stratico, Adam Yerkes, Kwon Moo Park, Alice M. Sheridan, Emad S. Alnemri, Joseph V. Bonventre, and Antonis S. Zervos. "Omi/HtrA2 protease mediates cisplatin-induced cell death in renal cells." American Journal of Physiology-Renal Physiology 288, no. 2 (February 2005): F371—F379. http://dx.doi.org/10.1152/ajprenal.00154.2004.

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Omi/HtrA2 is a mitochondrial proapoptotic serine protease that is able to induce both caspase-dependent and caspase-independent cell death. After apoptotic stimuli, Omi is released to the cytoplasm where it binds and cleaves inhibitor of apoptosis proteins. In this report, we investigated the role of Omi in renal cell death following cisplatin treatment. Using primary mouse proximal tubule cells, as well as established renal cell lines, we show that the level of Omi protein is upregulated after treatment with cisplatin. This upregulation is followed by the release of Omi from mitochondria to the cytoplasm and degradation of XIAP. Reducing the endogenous level of Omi protein using RNA interference renders renal cells resistant to cisplatin-induced cell death. Furthermore, we show that the proteolytic activity of Omi is necessary and essential for cisplatin-induced cell death in this system. When renal cells are treated with Omi's specific inhibitor, ucf-101, they become significantly resistant to cisplatin-induced cell death. Ucf-101 was also able to minimize cisplatin-induced nephrotoxic injury in animals. Our results demonstrate that Omi is a major mediator of cisplatin-induced cell death in renal cells and suggest a way to limit renal injury by specifically inhibiting its proteolytic activity.

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LEE, SUG HYUNG, JONG WOO LEE, HONG SUG KIM, SU YOUNG KIM, WON SANG PARK, SANG HO KIM, JUNG YOUNG LEE, and NAM JIN YOO. "Immunohistochemical analysis of Omi/HtrA2 expression in stomach cancer." APMIS 111, no. 5 (May 2003): 586–90. http://dx.doi.org/10.1034/j.1600-0463.2003.1110508.x.

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Behbahani, Homira, Pavel F. Pavlov, Birgitta Wiehager, Takeshi Nishimura, Bengt Winblad, and Maria Ankarcrona. "Association of Omi/HtrA2 with γ-secretase in mitochondria." Neurochemistry International 57, no. 6 (November 2010): 668–75. http://dx.doi.org/10.1016/j.neuint.2010.08.004.

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Wu, Linguo, Dan Liu, Ye Wu, Xin Wei, Zhaojia Wang, Wen Wang, Suli Zhang, Hong Yang, Ming Yi, and Huirong Liu. "p53 mediated transcription of Omi/HtrA2 in aging myocardium." Biochemical and Biophysical Research Communications 519, no. 4 (November 2019): 734–39. http://dx.doi.org/10.1016/j.bbrc.2019.09.062.

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Twiddy, Davina, David G. Brown, Colin Adrain, Rebekah Jukes, Seamus J. Martin, Gerald M. Cohen, Marion MacFarlane, and Kelvin Cain. "Pro-apoptotic Proteins Released from the Mitochondria Regulate the Protein Composition and Caspase-processing Activity of the Native Apaf-1/Caspase-9 Apoptosome Complex." Journal of Biological Chemistry 279, no. 19 (March 1, 2004): 19665–82. http://dx.doi.org/10.1074/jbc.m311388200.

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The apoptosome is a large caspase-activating (∼700–1400 kDa) complex, which is assembled from Apaf-1 and caspase-9 when cytochromecis released during mitochondrial-dependent apoptotic cell death. Apaf-1 the core scaffold protein is ∼135 kDa and contains CARD (caspaserecruitmentdomain), CED-4, and multiple (13) WD40 repeat domains, which can potentially interact with a variety of unknown regulatory proteins. To identify such proteins we activated THP.1 lysates with dATP/cytochromecand used sucrose density centrifugation and affinity-based methods to purify the apoptosome for analysis by MALDI-TOF mass spectrometry. First, we used a glutathioneS-transferase (GST) fusion protein (GST-casp91–130) containing the CARD domain of caspase-9-(1–130), which binds to the CARD domain of Apaf-1 when it is in the apoptosome and blocks recruitment/activation of caspase-9. This affinity-purified apoptosome complex contained only Apaf-1XL and GST-casp91–130, demonstrating that the WD40 and CED-4 domains of Apaf-1 do not stably bind other cytosolic proteins. Next we used a monoclonal antibody to caspase-9 to immunopurify the native active apoptosome complex from cell lysates, containing negligible levels of cytochromec,secondmitochondria-derivedactivator ofcaspase (Smac), or Omi/HtrA2. This apoptosome complex exhibited low caspase-processing activity and contained four stably associated proteins, namely Apaf-1, pro-p35/34 forms of caspase-9, pro-p20 forms of caspase-3, X-linkedinhibitor ofapoptosis (XIAP), and cytochromec, which was only bound transiently to the complex. However, in lysates containing Smac and Omi/HtrA2, the caspase-processing activity of the purified apoptosome complex increased 6–8-fold and contained only Apaf-1 and the p35/p34-processed subunits of caspase-9. During apoptosis, Smac, Omi/HtrA2, and cytochromecare released simultaneously from mitochondria, and thus it is likely that the functional apoptosome complex in apoptotic cells consists primarily of Apaf-1 and processed caspase-9.

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Silke, John, Christine J. Hawkins, Paul G. Ekert, Joanne Chew, Catherine L. Day, Miha Pakusch, Anne M. Verhagen, and David L. Vaux. "The anti-apoptotic activity of XIAP is retained upon mutation of both the caspase 3– and caspase 9–interacting sites." Journal of Cell Biology 157, no. 1 (April 1, 2002): 115–24. http://dx.doi.org/10.1083/jcb.200108085.

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The X-linked mammalian inhibitor of apoptosis protein (XIAP) has been shown to bind several partners. These partners include caspase 3, caspase 9, DIABLO/Smac, HtrA2/Omi, TAB1, the bone morphogenetic protein receptor, and a presumptive E2 ubiquitin-conjugating enzyme. In addition, we show here that XIAP can bind to itself. To determine which of these interactions are required for it to inhibit apoptosis, we generated point mutant XIAP proteins and correlated their ability to bind other proteins with their ability to inhibit apoptosis. ∂RING point mutants of XIAP were as competent as their full-length counterparts in inhibiting apoptosis, although impaired in their ability to oligomerize with full-length XIAP. Triple point mutants, unable to bind caspase 9, caspase 3, and DIABLO/HtrA2/Omi, were completely ineffectual in inhibiting apoptosis. However, point mutants that had lost the ability to inhibit caspase 9 and caspase 3 but retained the ability to inhibit DIABLO were still able to inhibit apoptosis, demonstrating that IAP antagonism is required for apoptosis to proceed following UV irradiation.

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Bhuiyan, Md, and Kohji Fukunaga. "Mitochondrial Serine Protease HtrA2/Omi as a Potential Therapeutic Target." Current Drug Targets 10, no. 4 (April 1, 2009): 372–83. http://dx.doi.org/10.2174/138945009787846399.

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Goo, Hui-Gwan, Hyangshuk Rhim, and Seongman Kang. "Pathogenic Role of Serine Protease HtrA2/Omi in Neurodegenerative Diseases." Current Protein & Peptide Science 18, no. 7 (May 8, 2017): 746–57. http://dx.doi.org/10.2174/1389203717666160311115750.

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Suzuki, Y., K. Takahashi-Niki, T. Akagi, T. Hashikawa, and R. Takahashi. "Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways." Cell Death & Differentiation 11, no. 2 (November 7, 2003): 208–16. http://dx.doi.org/10.1038/sj.cdd.4401343.

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Goo, Hui-Gwan, Min Kyo Jung, Sung Sic Han, Hyangshuk Rhim, and Seongman Kang. "HtrA2/Omi deficiency causes damage and mutation of mitochondrial DNA." Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1833, no. 8 (August 2013): 1866–75. http://dx.doi.org/10.1016/j.bbamcr.2013.03.016.

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Zurawa-Janicka, Dorota, Miroslaw Jarzab, Agnieszka Polit, Joanna Skorko-Glonek, Adam Lesner, Agata Gitlin, Artur Gieldon, et al. "Temperature-induced changes of HtrA2(Omi) protease activity and structure." Cell Stress and Chaperones 18, no. 1 (August 1, 2012): 35–51. http://dx.doi.org/10.1007/s12192-012-0355-1.

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Seong, Young-Mo, Hyo-Jin Park, Geun-Hye Seong, Ju-Youn Choi, Sung-Joo Kim Yoon, Byung-Re Min, Seongman Kang, and Hyangshuk Rhim. "N-terminal truncation circumvents proteolytic degradation of the human HtrA2/Omi serine protease in Escherichia coli: rapid purification of a proteolytically active HtrA2/Omi." Protein Expression and Purification 33, no. 2 (February 2004): 200–208. http://dx.doi.org/10.1016/j.pep.2003.10.002.

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Gambardella, Stefano, Rosangela Ferese, Simona Scala, Stefania Carboni, Francesca Biagioni, Giardina Emiliano, Stefania Zampatti, et al. "Mitochondrial Serine Protease HTRA2 p.G399S in a Female with Di George Syndrome and Parkinson’s Disease." Parkinson's Disease 2018 (June 21, 2018): 1–6. http://dx.doi.org/10.1155/2018/5651435.

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Deletion at 22q11.2 responsible for Di George syndrome (DGs) is a risk factor for early-onset Parkinson’s disease (EOPD). To date, all patients reported with 22q11.2 deletions and parkinsonian features are negative for a family history of PD, and possible mutations in PD-related genes were not properly evaluated. The goal of this paper was to identify variants in PD genes that could contribute, together with 22q11.2 del, to the onset of parkinsonian features in patients affected by Di George syndrome. To this aim, sequencing analysis of 4800 genes including 17 PD-related genes was performed in a patient affected by DGs and EOPD. The analysis identified mutation p.Gly399Ser in OMI/HTRA2 (PARK13). To date, the mechanism that links DGs with parkinsonian features is poorly understood. The identification of a mutation in a PARK gene suggests that variants in PD-related genes, or in genes still not associated with PD, could contribute, together with deletion at 22q11.2, to the EOPD in patients affected by DGs. Further genetic analyses in a large number of patients are strongly required to understand this mechanism and to establish the pathogenetic role of p.Gly399Ser in OMI/HTRA2.

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Wang, Chi-Yun, Yee-Shin Lin, Wu-Chou Su, Chia-Ling Chen, and Chiou-Feng Lin. "Glycogen Synthase Kinase-3 and Omi/HtrA2 Induce Annexin A2 Cleavage followed by Cell Cycle Inhibition and Apoptosis." Molecular Biology of the Cell 20, no. 19 (October 2009): 4153–61. http://dx.doi.org/10.1091/mbc.e09-02-0174.

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Annexin A2 is involved in multiple cellular processes, including cell survival, growth, division, and differentiation. A lack of annexin A2 makes cells more sensitive to apoptotic stimuli. Here, we demonstrate a potential mechanism for apoptotic stimuli-induced annexin A2 cleavage, which contributes to cell cycle inhibition and apoptosis. Annexin A2 was persistently expressed around the proliferative but not the necrotic region in BALB/c nude mice with human lung epithelial carcinoma cell A549-derived tumors. Knockdown expression of annexin A2 made cells susceptible to either serum withdrawal-induced cell cycle inhibition or cisplatin-induced apoptosis. Under apoptotic stimuli, annexin A2 was time-dependently cleaved. Mechanistic studies have shown that protein phosphatase 2A (PP2A)-activated glycogen synthase kinase (GSK)-3 is essential for this process. Therefore, inhibiting GSK-3 reversed serum withdrawal-induced cell cycle inhibition and cisplatin-induced apoptosis. Furthermore, inhibiting serine proteases blocked apoptotic stimuli-induced annexin A2 cleavage. Bax activation and Mcl-1 destabilization, which is regulated by PP2A and GSK-3, caused annexin A2 cleavage via an Omi/HtrA2-dependent pathway. Taking these results together, we conclude that GSK-3 and Omi/HtrA2 synergistically cause annexin A2 cleavage and then cell cycle inhibition or apoptosis.

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Bowden, M. A., L. A. Di Nezza, T. Jobling, L. A. Salamonsen, and G. Nie. "284.Expression of HtrA1, 2 and 3 in human endometrial cancer." Reproduction, Fertility and Development 16, no. 9 (2004): 284. http://dx.doi.org/10.1071/srb04abs284.

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The mammalian HtrA family consists of serine proteases with distinct domains homologous to the bacterial high temperature requirement factor (HtrA). Three human HtrA members have been reported: HtrA1 (PRSS11 or L56), HtrA2 (OMI) and HtrA3 (PRSP). The function of HtrA1 is not well characterised, but it has been shown to be downregulated in malignant tissues (1–3) indicating that the downregulation of HtrA1 is associated with cancer progression. HtrA2 regulates apoptosis by interacting with X-linked inhibitors of apoptosis (XIAP) thus preventing the caspase-inhibitory function of XIAP (4). The function of newly identified HtrA3 is not known, however it shares a high degree of sequence and domain homologies with HtrA1 and may therefore share a functional similarity with HtrA1 (5). Endometrial cancer (EC) is a prevalent gynaecological cancer, commonly affecting women after menopause. In this study we examined the expression of HtrA1, 2 and 3 in EC. Reverse transcriptase-PCR (semi-quantitative) analysis showed decreased mRNA expression of both HtrA1 and HtrA3, but no significant change for HtrA2, in EC tissue samples compared to normal endometrium. We then determined the protein level of expression and the cellular localisation of all three HtrA members in EC progression using immunohistochemistry. HtrA1 and HtrA3 showed a similar pattern of expression and both decreased dramatically with the progression of cancer from grade 1 through to 3. Surprisingly, HtrA2 protein expression was also decreased with cancer progression, but the decline was not as dramatic as that for HtrA1 and HtrA3. Interestingly, considerably less staining was observed for all three HtrA proteins in grade 3 cancer tissues. These data suggest that decreased expression of HtrA proteins, particularly HtrA1 and HtrA3, is associated with the progression of endometrial cancer. (1) Nie, G., Hampton, A., Li, Y., Findlay, J., Salamonsen, L.A. (2003) Identification and cloning of two isoforms of human high-temperature requirement factor A3 (HtrA3), characterization of its genomic structure and comparison of its tissue distribution with HtrA1 and HtrA2. Biochem. J. 371, 39–48. (2) van Loo, G., van Gurp, M., Depuydt, B., Srinivasula, S.M., Rodriguez, I., Alnemri, E.S., Gevaert, K., Vandekerckhove, J., Declercq, W., Vandenabeele, P. (2002) The serine protease OMI/HtrA2 is released from mitochondria during apoptosis. OMI interacts with caspase-inhibitor XIAP and induces enhanced caspase activity. Cell Death Diff. 9, 20–26. (3) Chien, J., Staub, J., Hu, S., Erickson-Johnson, M.R., Couch, F.J., Smith, D.I., Crowl, R.M., Kaufmann, S., Shridhar, V. (2004) A candidate tumour supressor HtrA1 is down-regulated in ovarian cancer. Oncogene 23, 1636–1644. (4) Shridhar, V., Sen, A., Chien, J., Staub, J., Avula, R., Kovats, S., Lee, J., Lillie, J., Smith, D.I. (2002) Identification of underexpressed genes in early- and late-stage primary ovarian tumours by suppression subtraction hybridization. Cancer Res. 62, 262–270. (5) Baldi, A., De Luca, A., Morini, M., Battista, T., Felsani, A., Baldi, F., Catricala, C., Amantea, A., Noonan, D. M., Albini, A., Ciorgio, P., Lombardi, D., Paggi, M. G. (2002) The HtrA1 serine protease is down-regulated during human melanoma progression and represses growth of metastatic melanoma cells. Oncogene 21, 6684–6688.

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Markova, V. E., D. K. Shishkova, and A. G. Kutikhin. "Analysis of intrinsic apoptosis in endothelial cells exposed to calcium phosphate bions." Fundamental and Clinical Medicine 5, no. 3 (September 30, 2020): 50–58. http://dx.doi.org/10.23946/2500-0764-2020-5-3-50-58.

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Aim. To study intrinsic apoptosis in primary arterial endothelial cells treated with calcium phosphate bions (CPB). Materials and Methods. Primary human coronary artery endothelial cells were exposed to spherical or needle-shaped CPB during 4 hours with the subsequent extraction of total protein and subcellular fractionation to separate mitochondrial and cytosolic protein. We then performed Western blotting to measure the relative levels of a mitochondrial marker porin, cytosolic marker glyceraldehyde 3-phosphate dehydrogenase and intrinsic apoptosis proteins cytochrome c and HtrA2/Omi in mitochondria and cytosol in addition to the levels of total and cleaved caspases-9 and caspases-3 in the total protein collected from three independent experiments. Results. Translocation of cytochrome c and HtrA2/Omi was not a mandatory consequence of CPB exposure. Relative levels of the measured proteins differed according to the particle shape. Out of three experiments, only one showed a significant increase in cleaved caspase-9 and caspase-3 in CPB-treated as compared with the mock-treated cells. In other experiments, cleaved caspases did not show a consistent elevation. The levels of total and cleaved caspase-9 and caspases-3 were concordant testifying to the direct correlation between them. Conclusion. As mechanisms of CPB-induced endothelial toxicity are poorly defined, they require further investigation employing optimized methods.

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Liu, Dan, Xin Liu, Ye Wu, Wen Wang, Xinliang Ma, and Huirong Liu. "Cloning and Transcriptional Activity of the Mouse Omi/HtrA2 Gene Promoter." International Journal of Molecular Sciences 17, no. 1 (January 16, 2016): 119. http://dx.doi.org/10.3390/ijms17010119.

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Kawamoto, Yasuhiro, Hidefumi Ito, Yoshito Kobayashi, Yasuyuki Suzuki, and Ryosuke Takahashi. "Localization of HtrA2/Omi immunoreactivity in brains affected by Alzheimer’s disease." NeuroReport 21, no. 17 (December 2010): 1121–25. http://dx.doi.org/10.1097/wnr.0b013e328340a731.

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Sosna, Justyna, Susann Voigt, Sabine Mathieu, Dieter Kabelitz, Ahmad Trad, Ottmar Janssen, Catherine Meyer-Schwesinger, Stefan Schütze, and Dieter Adam. "The proteases HtrA2/Omi and UCH-L1 regulate TNF-induced necroptosis." Cell Communication and Signaling 11, no. 1 (2013): 76. http://dx.doi.org/10.1186/1478-811x-11-76.

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Kang, Seokwon, Teresa Fernandes-Alnemri, and Emad S. Alnemri. "A novel role for the mitochondrial HTRA2/OMI protease in aging." Autophagy 9, no. 3 (March 7, 2013): 420–21. http://dx.doi.org/10.4161/auto.22920.

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Kuninaka, S., S.-I. Iida, T. Hara, M. Nomura, H. Naoe, T. Morisaki, M. Nitta, et al. "Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation." Oncogene 26, no. 17 (November 20, 2006): 2395–406. http://dx.doi.org/10.1038/sj.onc.1210042.

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Xu, Jiahui, Kun Jiao, Xin Liu, Qi Sun, Ke Wang, Haibo Xu, Shangyue Zhang, et al. "Omi/HtrA2 Participates in Age-Related Autophagic Deficiency in Rat Liver." Aging and disease 9, no. 6 (2018): 1031. http://dx.doi.org/10.14336/ad.2018.0221.

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Wang, Chun-yu, Qian Xu, Ling Weng, Qiang Zhang, Hai-nan Zhang, Ji-feng Guo, Li-Ming Tan, Jian-guang Tang, Xin-xiang Yan, and Bei-sha Tang. "Genetic variations of Omi/HTRA2 in Chinese patients with Parkinson's disease." Brain Research 1385 (April 2011): 293–97. http://dx.doi.org/10.1016/j.brainres.2011.02.037.

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Napolitano, Filomena, Chiara Terracciano, Giorgia Bruno, Claudia Nesti, Maria R. Barillari, Umberto Barillari, Filippo M. Santorelli, Mariarosa A. B. Melone, Teresa Esposito, and Simone Sampaolo. "Intrafamilial “DOA‐plus” phenotype variability related to different OMI/HTRA2 expression." American Journal of Medical Genetics Part A 182, no. 1 (October 14, 2019): 176–82. http://dx.doi.org/10.1002/ajmg.a.61381.

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Okada, Masayuki, Souichi Adachi, Tsuyoshi Imai, Ken-ichiro Watanabe, Shin-ya Toyokuni, Masaki Ueno, Antonis S. Zervos, Guido Kroemer, and Tatsutoshi Nakahata. "A novel mechanism for imatinib mesylate–induced cell death of BCR-ABL–positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity." Blood 103, no. 6 (March 15, 2004): 2299–307. http://dx.doi.org/10.1182/blood-2003-05-1605.

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Abstract Caspase-independent programmed cell death can exhibit either an apoptosis-like or a necrosis-like morphology. The ABL kinase inhibitor, imatinib mesylate, has been reported to induce apoptosis of BCR-ABL–positive cells in a caspase-dependent fashion. We investigated whether caspases alone were the mediators of imatinib mesylate–induced cell death. In contrast to previous reports, we found that a broad caspase inhibitor, zVAD-fmk, failed to prevent the death of imatinib mesylate–treated BCR-ABL–positive human leukemic cells. Moreover, zVAD-fmk–preincubated, imatinib mesylate–treated cells exhibited a necrosis-like morphology characterized by cellular pyknosis, cytoplasmic vacuolization, and the absence of nuclear signs of apoptosis. These cells manifested a loss of the mitochondrial transmembrane potential, indicating the mitochondrial involvement in this caspase-independent necrosis. We excluded the participation of several mitochondrial factors possibly involved in caspase-independent cell death such as apoptosis-inducing factor, endonuclease G, and reactive oxygen species. However, we observed the mitochondrial release of the serine protease Omi/HtrA2 into the cytosol of the cells treated with imatinib mesylate or zVAD-fmk plus imatinib mesylate. Furthermore, serine protease inhibitors prevented the caspase-independent necrosis. Taken together, our results suggest that imatinib mesylate induces a caspase-independent, necrosis-like programmed cell death mediated by the serine protease activity of Omi/HtrA2.

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Bishop, Matthew W., Subhojit Chakraborty, Gillian A. C. Matthews, Antonios Dougalis, Nicholas W. Wood, Richard Festenstein, and Mark A. Ungless. "Hyperexcitable Substantia Nigra Dopamine Neurons in PINK1- and HtrA2/Omi-Deficient Mice." Journal of Neurophysiology 104, no. 6 (December 2010): 3009–20. http://dx.doi.org/10.1152/jn.00466.2010.

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The electrophysiological properties of substantia nigra pars compacta (SNC) dopamine neurons can influence their susceptibility to degeneration in toxin-based models of Parkinson's disease (PD), suggesting that excitotoxic and/or hypoactive mechanisms may be engaged during the early stages of the disease. It is unclear, however, whether the electrophysiological properties of SNC dopamine neurons are affected by genetic susceptibility to PD. Here we show that deletion of PD-associated genes, PINK1 or HtrA2/Omi, leads to a functional reduction in the activity of small-conductance Ca2+-activated potassium channels. This reduction causes SNC dopamine neurons to fire action potentials in an irregular pattern and enhances burst firing in brain slices and in vivo. In contrast, PINK1 deletion does not affect firing regularity in ventral tegmental area dopamine neurons or substantia nigra pars reticulata GABAergic neurons. These findings suggest that changes in SNC dopamine neuron excitability may play a role in their selective vulnerability in PD.

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Yan, Ying, Xiaoni Lv, Jun Ma, Ganji Hong, Shikai Li, Jiahao Shen, Haotian Chen, et al. "Simvastatin Alleviates Intestinal Ischemia/Reperfusion Injury by Modulating Omi/HtrA2 Signaling Pathways." Transplantation Proceedings 51, no. 8 (October 2019): 2798–807. http://dx.doi.org/10.1016/j.transproceed.2019.04.076.

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Pavlov, Pavel F. "P4-197: Regulation of HtrA2/Omi activity by the mitochondrial γ-secretase." Alzheimer's & Dementia 4 (July 2008): T729. http://dx.doi.org/10.1016/j.jalz.2008.05.2264.

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