3.4.21.108	malfunction	decreased enzyme function damages mitochondrial quality in the heterozygous mouse brain cortex, leading to more brain ischemia/reperfusion injury. HtrA2-heterozygous mice show decreased mitochondrial quality control and reduced mitochondrial function after ischemia/reperfusion injury, decreased anti-damage ability and increased apoptosis after middle cerebral artery occlusion	771822	
3.4.21.108	malfunction	endogenous levels of Parkin are significantly decreased in wild-type (HtrA2+/+) mouse embryonic fibroblasts compared with those in HtrA2-knockout (HtrA2-/-) mouse embryonic fibroblasts under the same stress conditions	707374	
3.4.21.108	malfunction	enzyme inactivation leads to the growth retardation of adipocytes, thereby delaying the hair cycle of mnd2 mice	769073	
3.4.21.108	malfunction	fewer and abnormal mitochondria are found in HtrA2/Omi knockout mice photoreceptors and pigment epithelial cells	708821	
3.4.21.108	malfunction	in mouse embryonic HtrA2/omi knockout fibroblast cells the apoptosis-dependent cleavage of Wilms'tumor suppressor protein WT1 is prevented and expression of WT1 is upregulated	709955	
3.4.21.108	malfunction	in Omi/HtrA2 knockout mouse embryonic fibroblasts elongated mitochondria are found by live cell imaging. Electron microscopy confirm the mitochondrial morphology alterations and show abnormal cristae structure. Examining the levels of proteins involved in mitochondrial fusion, a selective up-regulation of optic atrophy protein 1 is shown. Complementation of knockout cells with human wild-type Omi/HtrA2 reverses the mitochondrial elongation phenotype and optic atrophy protein 1 alterations	708415	
3.4.21.108	malfunction	in Omi/HtrA2 silenced Drosophila S2R+ cells elongated mitochondria are found by live cell imaging. Electron microscopy confirm the mitochondrial morphology alterations and show abnormal cristae structure. Examining the levels of proteins involved in mitochondrial fusion, a selective up-regulation of optic atrophy protein 1 is shown	708415	
3.4.21.108	malfunction	in Omi/HtrA2 silenced human HeLa elongated mitochondria are found by live cell imaging. Electron microscopy confirm the mitochondrial morphology alterations and show abnormal cristae structure. Examining the levels of proteins involved in mitochondrial fusion, a selective up-regulation of optic atrophy protein 1 is shown	708415	
3.4.21.108	malfunction	knockdown of HtrA2/Omi affords protection against interleukin-3 withdrawal-induced death in the presence of carbobenzoxy-valyl-analylaspartyl-[O-methyl]-fluoromethylketone	717463	
3.4.21.108	malfunction	knockdown of Omi decreases the basal level of autophagy and increases the level of neurodegenerative proteins such as pathogenic A53T alpha-synuclein and truncated polyglutamine-expanded huntingtin, as well as the endogenous autophagy substrate p62	711699	
3.4.21.108	malfunction	loss of mitochondrial Omi/HtrA2 is associated with S-nitrosoglutathione-induced apoptosis in human endothelial cells	713539	
3.4.21.108	malfunction	Omi/HtrA2 knockout mice show significant increase in intramitochondrial reactive oxygen species and decreased mitochondrial membrane potential in MEF cells	708415	
3.4.21.108	malfunction	transient enzyme knock-down inhibits parasite growth, disrupts the intra-erythrocytic parasite cycle, and affects mitochondria development	775403	
3.4.21.108	metabolism	the enzyme cleaves vimentin and affects vimentin assembly and polymerization following irradiation	774369	
3.4.21.108	physiological function	cytosolic HtrA2 decreases ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) protein level and its hydrolase activity through HtrA2-mediated cleavage of UCH-L1 under apoptotic conditions. HtrA2-mediated cleavage of UCH-L1 plays important roles in regulating the fine balance between cell growth and cell death	717200	
3.4.21.108	physiological function	during thermal activation, the PDZ domain changes its position versus the protease domain inside a subunit, including a prominent change affecting the L3 regulatory loop of the protease domain, and also changes its interactions with the protease domain of the adjacent subunit, specifically with its L1* regulatory loop containing the active site serine. The alpha5 helix of PDZ is involved in both, the intra- and intersubunit changes of interactions and seems to play an important role in HtrA2 activation	752820	
3.4.21.108	physiological function	HtrA2 acts as an apoptotic factor which targets inhibitors of apoptosis during apoptosis, and thereby enhances caspase activation and caspase-mediated cell death	717632	
3.4.21.108	physiological function	HtrA2 has a moderate ability to delay the aggregation of citrate synthase in vitro. Additionally, using electron microscopy and nuclear magnetic resonance analyses, it is observed that HtrA2 significantly delays the aggregation of the Abeta1-42 peptide. The protease activity of HtrA2 and its PDZ domain are not essential for the delay of Abeta1-42 peptide aggregation	708862	
3.4.21.108	physiological function	HtrA2 under several different stress conditions induces cleavage of vimentin in wild-type as well as SH-SY5Y cells transfected with amyloid precursor protein with the Alzheimer disease-associated Swedish mutation. After stress treatment, inhibition of HtrA2 protease activity by the specific inhibitor, Ucf-101, reduces the cleavage of vimentin in wild-type cells	754775	
3.4.21.108	physiological function	HtrA2/Omi cleave Wilms'tumor suppressor protein WT1 which causes the removal of WT1 from its binding sites at gene promoters, leading to alterations in gene regulation that enhance apoptosis	709955	
3.4.21.108	physiological function	HtrA2/Omi plays a role in caspase-independent cell death during growth factor withdrawal by cleaving receptor-interacting protein 1	717463	
3.4.21.108	physiological function	it is analyzed whether abnormal expression of HtrA2/Omi occurs in amyotrophic lateral sclerosis patients: abnormal accumulations of HtrA2/Omi may occur in several types of motor neuronal inclusions in the anterior horn from sporadic amyotrophic lateral sclerosis and Cu/Zn superoxide dismutase (SOD1)-related familial amyotrophic lateral sclerosis (FALS) cases, and that HtrA2/Omi may be associated with the pathogenesis of both types of amyotrophic lateral sclerosis	710093	
3.4.21.108	physiological function	Omi activates autophagy in a dose-dependent manner through digestion of Hax-1, Omi-induced autophagy facilitates the degradation of neurodegenerative proteins such as pathogenic A53T alpha-synuclein and truncated polyglutamine-expanded huntingtin, as well as the endogenous autophagy substrate p62. Omi is important in the cellular quality control of proteins involved in neurodegenerative diseases	711699	
3.4.21.108	physiological function	Omi/HtrA2 functionally and physically interacts with the mitochondrial fusion protein OPA1. Mitochondrial morphology relies on Omi/HtrA2 protease function	708415	
3.4.21.108	physiological function	Omi/HtrA2 interacts with thanatos-associated protein 5 in mammalian cells during apoptosis	707066	
3.4.21.108	physiological function	Omi/HtrA2 is released from mitochondria to the cytosol and is required for annexin A2 cleavage under apoptotic stimuli	709872	
3.4.21.108	physiological function	pharmacological inhibition or genetic deletion of enzyme HtrA2/Omi protects from TNF-induced necroptosis. HtrA2/Omi does not cleave ubiquitin C-terminal hydrolase UCH-L1 during TNF-induced necroptosis, but rather induces monoubiquitination indicative for UCH-L1 activation. Correspondingly, pharmacologic or RNA interference-mediated inhibition of UCH-L1 protects from TNF-induced necroptosis	731595	
3.4.21.108	physiological function	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 are released from mitochondria into the platelet cytosol together with cytochrome c after induction of apoptosis by theCa2+ ionophore A23187 or the BH3 mimetic ABT-737, and to a lesser extent, after platelet stimulation with collagen and thrombin	732929	
3.4.21.108	physiological function	protease HtrA2 restricts the activation of apoptosis-associated speck-like protein containing a caspase-recruitment domain, i.e. ASC, dependent NLRP3 and AIM2 inflammasomes, in a protease activity-dependent manner. Disruption of the protease activity of HtrA2 results in exacerbated NLRP3 and AIM2 inflammasome responses in macrophages ex vivo and systemically in vivo. HtrA2 protease activity regulates autophagy and controls the magnitude and duration of inflammasome signaling by preventing prolonged accumulation of the inflammasome adaptor ASC	755509	
3.4.21.108	physiological function	proteolysis of Wilms' tumor suppressor 1 by HtrA2 causes the removal of WT1 from its binding sites at gene promoters, leading to alterations in gene regulation that enhance apoptosis	709955	
3.4.21.108	physiological function	silencing endogenous expression of HtrA2/Omi with siRNA results in aggregated endoplasmic reticulum stress and cell death. The expression level of HtrA2/Omi decreases with endoplasmic reticulum stress induction in 6-hydroxydopamine-treated SH-SY5Y cells	732357	
3.4.21.108	physiological function	the enzyme is involved in the cytoskeletal reorganization that accompanies radiation-induced senescence and the continuous maintenance of proliferation arrest	774369	
3.4.21.108	physiological function	the enzyme plays a crucial role in apoptosis by cleaving inhibitory and anti-apoptotic proteins by translocating from mitochondria to the cytosol	768982	
3.4.21.108	physiological function	the enzyme plays a dual role in maintenance of parasite mitochondria under normal conditions, as well as regulation of programmed cell death under cellular stress conditions. The enzyme activity is not essential for parasite survival	775403	
3.4.21.108	physiological function	the enzyme plays an essential role in regulating the adipogenesis-associated hair cycle	769073	
3.4.21.108	physiological function	the HtrA2-mediated Parkin cleavage irreversibly disrupts Parkin-mediated synphilin-1 ubiquitination and autoubiquitination, indicating that HtrA2 may play a critical role in the Parkin-related pathway involved in the ubiquitin proteasome system	707374	
3.4.21.108	physiological function	The inhibition of HtrA2 by specific inhibitor UCF-101 or by shRNA reduces lipopolysaccharide-induced brain endothelial cell apoptosis, and results in significant improvement on lipopolysaccharide-induced blood-brain-barrier disruption as well as decreased occludin, claudin-5 and ZO-1 expressions. HtrA2 manipulates endothelial cell apoptosis by shifting into cytosol and inducing X-linked inhibitor of apoptosis protein (XIAP) degradation. UCF-101 administration or HtrA2 shRNA intervention attenuates the degradation of XIAP, poly-ADP-ribose polymerase (PARP), cleavage, and caspase-3 cleavage. UCF-101 partly prevents the mobilization of HtrA2 from the mitochondria to the cytosol after lipopolysaccharide intervention	753695	
3.4.21.108	physiological function	the PDZ domain is dispensable for HtrA3 activity	755093