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

• The serine protease Omi/HtrA2 is involved in XIAP cleavage and in neuronal cell death following focal cerebral ischemia/reperfusion [2].
• Cytosolic HtrA2/Omi level increased while Xiap was downregulated in cisplatin-resistant ovarian cancer cells [3].
• To examine the role of the Omi/HtrA2 pathway and its relationship to oxidative stress after reperfusion following cerebral ischemia, we used a transient focal cerebral ischemia (tFCI) model in copper/zinc-superoxide dismutase (SOD1) transgenic mice and wild-type mice [11].
• In the OMI group, % T1 uptake and washout rates in the infarction areas improved significantly from 52.4% and 0.25 before nicorandil to 60.4% and 0.38 after it [12].

Biological context of HTRA2

• A catalytically inactive mutant of HtrA2, however, does not induce cell death [10].
• Direct IAP binding protein with low pI/second mitochondrial activator of caspases, HtrA2/Omi and GstPT/eRF3 are mammalian proteins that bind via N-terminal inhibitor of apoptosis protein (IAP) binding motifs (IBMs) to the baculoviral IAP repeat (BIR) domains of IAPs [13].
• Suppression of Omi/HtrA2 by RNA interference in human cell lines reduces cell death in response to TRAIL and etoposide [14].
• In contrast, ectopic expression of mature wildtype Omi/HtrA2, but not an active site mutant, induces potent caspase activation and apoptosis [14].
• Focal cerebral ischemia/reperfusion induced a mitochondrial up-regulation of Omi/HtrA2 and significantly increased cytosolic accumulation of Omi/HtrA2 [2].

Anatomical context of HTRA2

• Omi/HtrA2 is a mitochondrial serine protease that is released into the cytosol during apoptosis to antagonize inhibitors of apoptosis (IAPs) and contribute to caspase-independent cell death [9].
• A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death [10].
• Extramitochondrial expression of Omi/HtrA2 indirectly induced permeabilization of the outer mitochondrial membrane and subsequent Cyt c-dependent caspase activation in HeLa cells [15].
• Interestingly, the level of C161 was remarkably decreased in motor neuron degeneration (mnd2) mice in which the serine protease activity of HtrA2 was greatly reduced [16].
• Intramitochondrial serine protease activity of Omi/HtrA2 is required for caspase-independent cell death of human neutrophils [17].

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

• Using yeast two-hybrid assays, we found that Abeta interacts with HtrA2/Omi, an essential human serine protease with proapoptotic activity [22].
• The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif [23].
• Alzheimer's disease-associated amyloid beta interacts with the human serine protease HtrA2/Omi [22].

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

• The C-terminal tail of presenilin regulates Omi/HtrA2 protease activity [25].
• Cytosolic HtrA2/Omi level is partly regulated by Xiap in ovarian cancer cells [3].
• 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 [26]?

Other interactions of HTRA2

• 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 [25].
• As a result, three important regulators of apoptosis, Smac, HtrA2, and TRAF2, and three other proteins were identified as potential API2-MALT1-binding proteins [27].
• The interaction of Abeta with HtrA2/Omi was further confirmed through in vivo co-immunoprecipitation assay in HEK293 cells [22].
• The inhibitor-of-apoptosis protein Bir1p protects against apoptosis in S. cerevisiae and is a substrate for the yeast homologue of Omi/HtrA2 [28].
• Presence of the CLK2 kinase prevents the usage of exons 2 and 3, generating the htra2-beta3 mRNA [29].

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].

References