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Gene Review

HTRA2  -  HtrA serine peptidase 2

Homo sapiens

Synonyms: High temperature requirement protein A2, HtrA2, OMI, Omi stress-regulated endoprotease, PARK13, ...
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Disease relevance of HTRA2

  • Bax plays a pivotal role in thapsigargin-induced apoptosis of human colon cancer HCT116 cells by controlling Smac/Diablo and Omi/HtrA2 release from mitochondria [1].
  • However, the impact of Omi/HtrA2 in the apoptotic cell machinery that takes place in vivo under pathological conditions such as cerebral ischemia remains unknown [2].
  • Treatment of animals prior ischemia with ucf-101, the specific inhibitor of Omi/HtrA2, was able to (1) reduce the number of TUNEL-positive cells, to (2) attenuate the XIAP-breakdown and to (3) reduce the infarct size [2].
  • Regulation of HtrA2/Omi by X-linked inhibitor of apoptosis protein in chemoresistance in human ovarian cancer cells [3].
  • We analyzed its expression at protein, mRNA, and cellular levels using autopsy, biopsy, or operation LV samples from patients with failing hearts caused by acute (AMI) or old (OMI) myocardial infarction and idiopathic dilated cardiomyopathy (DCM) and also examined functional biochemical responses of failing hearts to Ang II [4].

Psychiatry related information on HTRA2

  • Limiting factors of a daily physical activity (DPA) in OMI were selected from various non-cardiac and cardiac factors by using multifactorial analysis (Hayashi III) [5].
  • These results rule out the involvement of HtrA2/Omi in the etiology of Alzheimer's disease [6].
  • The OMI questionnaire consisted of five factors: A) Authoritarianism, B) Benevolence, C) Mental Hygiene Ideology, D) Social Restrictiveness, and E) Interpersonal Etiology [7].

High impact information on HTRA2

  • Several caspase-independent death effectors including apoptosis-inducing factor, endonuclease G and a serine protease (Omi/HtrA2) are released from the mitochondrial intermembrane space upon permeabilization of the outer membrane [8].
  • Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis [9].
  • In short, HtrA2 is a Smac-like inhibitor of IAP activity with a serine protease-dependent cell death-inducing activity [10].
  • Here we report that a serine protease called HtrA2/Omi is released from mitochondria and inhibits the function of XIAP by direct binding in a similar way to Smac [10].
  • Moreover, when overexpressed extramitochondrially, HtrA2 induces atypical cell death, which is neither accompanied by a significant increase in caspase activity nor inhibited by caspase inhibitors, including XIAP [10].

Chemical compound and disease context of HTRA2


Biological context of HTRA2


Anatomical context of HTRA2


Associations of HTRA2 with chemical compounds

  • Treatment with ucf101, a serine protease HTRA2 specific inhibitor, counteracts IAPs degradation in HD cells and increases their survival [18].
  • 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 [19].
  • We have shown that the autocatalytic processing of HtrA2/Omi occurs via an intermolecular event, demonstrated by incubating an in vitro translated HtrA2/Omi (S306A) mutant with the enzymatically active glutathione S-transferase-HtrA2/Omi protein [20].
  • Using N-terminal amino acid sequencing and mutational analysis, we identified that the autocatalytic cleavage site is the carboxyl side of alanine 133 of HtrA2/Omi, resulting in exposure of an inhibitor of apoptosis protein binding motif in its N terminus [20].
  • Omi/HtrA2 protease mediates cisplatin-induced cell death in renal cells [21].

Physical interactions of HTRA2


Enzymatic interactions of HTRA2

  • In response to apoptotic stimuli, BRUCE is degraded by proteasomes and/or cleaved by caspases and HtrA2 depending on the specific stimulus and the cell type [24].

Regulatory relationships of HTRA2


Other interactions of HTRA2


Analytical, diagnostic and therapeutic context of HTRA2

  • Blocking the proteolytic activity of Omi/HtrA2 with specific inhibitors, such as the ucf-101, could be a novel way to afford neuroprotection and minimize cellular damage in cerebral ischemia/reperfusion [2].
  • Xiap content and cytosolic HtrA2/Omi content were analyzed by Western blot [3].
  • But in these adjusted models of length of stay: (1) diagnosis of OMI was not related to LOS, and (2) in the absence of a mental illness diagnosed at the visit, an identified history of either SMI or OMI was also not related to LOS [30].
  • In the current study, we analyzed the expression of Omi/HtrA2 in 60 advanced gastric adenocarcinomas by immunohistochemistry using a tissue microarray approach [31].
  • MATERIALS AND METHODS: Among 84 consecutive pHPT patients referred for surgery, 60 individuals with concordant localization of parathyroid adenoma on ultrasound and subtraction Tc(99m)-MIBI scintigraphy were found eligible for MIP under general anesthesia and were randomized to two groups (n = 30 each): MIVAP and OMIP [32].


  1. Bax plays a pivotal role in thapsigargin-induced apoptosis of human colon cancer HCT116 cells by controlling Smac/Diablo and Omi/HtrA2 release from mitochondria. Yamaguchi, H., Bhalla, K., Wang, H.G. Cancer Res. (2003) [Pubmed]
  2. The serine protease Omi/HtrA2 is involved in XIAP cleavage and in neuronal cell death following focal cerebral ischemia/reperfusion. Althaus, J., Siegelin, M.D., Dehghani, F., Cilenti, L., Zervos, A.S., Rami, A. Neurochem. Int. (2007) [Pubmed]
  3. Regulation of HtrA2/Omi by X-linked inhibitor of apoptosis protein in chemoresistance in human ovarian cancer cells. Yang, X., Xing, H., Gao, Q., Chen, G., Lu, Y., Wang, S., Ma, D. Gynecol. Oncol. (2005) [Pubmed]
  4. Angiotensin II type 2 receptor is upregulated in human heart with interstitial fibrosis, and cardiac fibroblasts are the major cell type for its expression. Tsutsumi, Y., Matsubara, H., Ohkubo, N., Mori, Y., Nozawa, Y., Murasawa, S., Kijima, K., Maruyama, K., Masaki, H., Moriguchi, Y., Shibasaki, Y., Kamihata, H., Inada, M., Iwasaka, T. Circ. Res. (1998) [Pubmed]
  5. An acute state of a daily physical activity in the chronic stage of myocardial infarction and a proposal of an optimal exercise therapy. Kamegai, M., Murayama, M., Sakakibara, M., Yamada, S., Tanabe, K., Sugai, J., Komazawa, T. Jpn. Circ. J. (1990) [Pubmed]
  6. HtrA2 interacts with A beta peptide but does not directly alter its production or degradation. Liu, M.L., Liu, M.J., Kim, J.M., Kim, H.J., Kim, J.H., Hong, S.T. Mol. Cells (2005) [Pubmed]
  7. Attitudes of Chinese and American male students towards mental illness. Shokoohi-Yekta, M., Retish, P.M. The International journal of social psychiatry. (1991) [Pubmed]
  8. Life's smile, death's grin: vital functions of apoptosis-executing proteins. Garrido, C., Kroemer, G. Curr. Opin. Cell Biol. (2004) [Pubmed]
  9. Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis. Yang, Q.H., Church-Hajduk, R., Ren, J., Newton, M.L., Du, C. Genes Dev. (2003) [Pubmed]
  10. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Suzuki, Y., Imai, Y., Nakayama, H., Takahashi, K., Takio, K., Takahashi, R. Mol. Cell (2001) [Pubmed]
  11. Modulation of the Omi/HtrA2 signaling pathway after transient focal cerebral ischemia in mouse brains that overexpress SOD1. Saito, A., Hayashi, T., Okuno, S., Nishi, T., Chan, P.H. Brain Res. Mol. Brain Res. (2004) [Pubmed]
  12. Study of the efficacy of nicorandil in patients with ischaemic heart disease using Exercise-T1-201 myocardial tomography. Yamazaki, J., Ohsawa, H., Uchi, T., Iida, M., Nakano, H., Hosoi, H., Morishita, T., Yabe, Y., Koyama, N., Komatsu, H. Eur. J. Clin. Pharmacol. (1993) [Pubmed]
  13. Identification of mammalian mitochondrial proteins that interact with IAPs via N-terminal IAP binding motifs. Verhagen, A.M., Kratina, T.K., Hawkins, C.J., Silke, J., Ekert, P.G., Vaux, D.L. Cell Death Differ. (2007) [Pubmed]
  14. Inhibitor of apoptosis proteins are substrates for the mitochondrial serine protease Omi/HtrA2. Srinivasula, S.M., Gupta, S., Datta, P., Zhang, Z., Hegde, R., Cheong, N., Fernandes-Alnemri, T., Alnemri, E.S. J. Biol. Chem. (2003) [Pubmed]
  15. Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways. Suzuki, Y., Takahashi-Niki, K., Akagi, T., Hashikawa, T., Takahashi, R. Cell Death Differ. (2004) [Pubmed]
  16. beta-Amyloid Precursor Protein Is a Direct Cleavage Target of HtrA2 Serine Protease: IMPLICATIONS FOR THE PHYSIOLOGICAL FUNCTION OF HtrA2 IN THE MITOCHONDRIA. Park, H.J., Kim, S.S., Seong, Y.M., Kim, K.H., Goo, H.G., Yoon, E.J., Min, d.o. .S., Kang, S., Rhim, H. J. Biol. Chem. (2006) [Pubmed]
  17. Intramitochondrial serine protease activity of Omi/HtrA2 is required for caspase-independent cell death of human neutrophils. Blink, E., Maianski, N.A., Alnemri, E.S., Zervos, A.S., Roos, D., Kuijpers, T.W. Cell Death Differ. (2004) [Pubmed]
  18. Prevention of cytosolic IAPs degradation: a potential pharmacological target in Huntington's Disease. Goffredo, D., Rigamonti, D., Zuccato, C., Tartari, M., Valenza, M., Cattaneo, E. Pharmacol. Res. (2005) [Pubmed]
  19. 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. Okada, M., Adachi, S., Imai, T., Watanabe, K., Toyokuni, S.Y., Ueno, M., Zervos, A.S., Kroemer, G., Nakahata, T. Blood (2004) [Pubmed]
  20. Autocatalytic processing of HtrA2/Omi is essential for induction of caspase-dependent cell death through antagonizing XIAP. Seong, Y.M., Choi, J.Y., Park, H.J., Kim, K.J., Ahn, S.G., Seong, G.H., Kim, I.K., Kang, S., Rhim, H. J. Biol. Chem. (2004) [Pubmed]
  21. Omi/HtrA2 protease mediates cisplatin-induced cell death in renal cells. Cilenti, L., Kyriazis, G.A., Soundarapandian, M.M., Stratico, V., Yerkes, A., Park, K.M., Sheridan, A.M., Alnemri, E.S., Bonventre, J.V., Zervos, A.S. Am. J. Physiol. Renal Physiol. (2005) [Pubmed]
  22. Alzheimer's disease-associated amyloid beta interacts with the human serine protease HtrA2/Omi. Park, H.J., Seong, Y.M., Choi, J.Y., Kang, S., Rhim, H. Neurosci. Lett. (2004) [Pubmed]
  23. The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. Martins, L.M., Iaccarino, I., Tenev, T., Gschmeissner, S., Totty, N.F., Lemoine, N.R., Savopoulos, J., Gray, C.W., Creasy, C.L., Dingwall, C., Downward, J. J. Biol. Chem. (2002) [Pubmed]
  24. The membrane-associated inhibitor of apoptosis protein, BRUCE/Apollon, antagonizes both the precursor and mature forms of Smac and caspase-9. Qiu, X.B., Goldberg, A.L. J. Biol. Chem. (2005) [Pubmed]
  25. The C-terminal tail of presenilin regulates Omi/HtrA2 protease activity. Gupta, S., Singh, R., Datta, P., Zhang, Z., Orr, C., Lu, Z., Dubois, G., Zervos, A.S., Meisler, M.H., Srinivasula, S.M., Fernandes-Alnemri, T., Alnemri, E.S. J. Biol. Chem. (2004) [Pubmed]
  26. Can application of serine protease inhibitors TPCK and TLCK provide evidence for possible involvement of serine protease Omi/HtrA2 in imatinib mesylate-induced cell death of BCR-ABL-positive human leukemia cells? Mlejnek, P. Leukemia (2005) [Pubmed]
  27. Antiapoptotic function of apoptosis inhibitor 2-MALT1 fusion protein involved in t(11;18)(q21;q21) mucosa-associated lymphoid tissue lymphoma. Hosokawa, Y., Suzuki, H., Suzuki, Y., Takahashi, R., Seto, M. Cancer Res. (2004) [Pubmed]
  28. The inhibitor-of-apoptosis protein Bir1p protects against apoptosis in S. cerevisiae and is a substrate for the yeast homologue of Omi/HtrA2. Walter, D., Wissing, S., Madeo, F., Fahrenkrog, B. J. Cell. Sci. (2006) [Pubmed]
  29. Human tra2-beta1 autoregulates its protein concentration by influencing alternative splicing of its pre-mRNA. Stoilov, P., Daoud, R., Nayler, O., Stamm, S. Hum. Mol. Genet. (2004) [Pubmed]
  30. Mental illness and length of inpatient stay for medicaid recipients with AIDS. Hoover, D.R., Sambamoorthi, U., Walkup, J.T., Crystal, S. Health services research. (2004) [Pubmed]
  31. Immunohistochemical analysis of Omi/HtrA2 expression in stomach cancer. Lee, S.H., Lee, J.W., Kim, H.S., Kim, S.Y., Park, W.S., Kim, S.H., Lee, J.Y., Yoo, N.J. APMIS (2003) [Pubmed]
  32. Minimally invasive video-assisted parathyroidectomy versus open minimally invasive parathyroidectomy for a solitary parathyroid adenoma: a prospective, randomized, blinded trial. Barczyński, M., Cichoń, S., Konturek, A., Cichoń, W. World journal of surgery. (2006) [Pubmed]
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