Affinage

HTRA2

Serine protease HTRA2, mitochondrial · UniProt O43464

Length
458 aa
Mass
48.8 kDa
Annotated
2026-06-10
100 papers in source corpus 47 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HTRA2/Omi is a mitochondrial intermembrane-space serine protease that functions both as a pro-apoptotic effector and as a constitutive guardian of mitochondrial protein quality control (PMID:11606597, PMID:15509788, PMID:25094062). It is synthesized with a mitochondrial targeting sequence whose removal, followed by intermolecular autocatalytic cleavage at Ala133, exposes an N-terminal Reaper/Smac-like IAP-binding motif (AVPS) (PMID:11602612, PMID:15201285). Upon apoptotic stimuli HTRA2 is released to the cytosol, where this motif binds the BIR3 domain of XIAP and related IAPs to relieve caspase inhibition, while its protease domain catalytically and irreversibly cleaves IAPs (including c-IAP1 and Apollon/BRUCE) — a more potent, non-stoichiometric mode of IAP inactivation than Smac/DIABLO antagonism (PMID:11606597, PMID:11604410, PMID:12815069, PMID:15781261). Full activity requires assembly into a pyramid-shaped homotrimer through the protease domains; monomeric mutants are proteolytically and pro-apoptotically dead, and the enzyme exchanges between this trimer and a low-activity hexamer, with activator-peptide binding triggering cooperative domain reorientation that exposes the catalytic center (PMID:11967569, PMID:33692127). The PDZ domain governs activity by recognizing exposed hydrophobic C-terminal and internal sequences of misfolded or partner proteins, and engagement by ligands such as presenilin-1's C-tail, Mpv17l, and the LATS1/WARTS kinase converts the latent enzyme to its active state (PMID:15294909, PMID:17656586, PMID:18772386, PMID:16007220, PMID:17130845). Beyond apoptosis, HTRA2 protease activity sustains mitochondrial homeostasis by degrading substrates including HAX-1, Mulan, prohibitin, and OPA1-regulatory targets, thereby controlling membrane potential, cristae morphology, mtDNA integrity, mitophagy, and biogenesis, while also processing a broad substrate range encompassing WT1, Parkin, RIP1, MEK1, GSK3β, p73α, APP, and β-actin to influence transcription, signaling, inflammation, and cytoskeletal dynamics (PMID:15371414, PMID:16968707, PMID:20122399, PMID:20064504, PMID:20125124, PMID:22912494, PMID:24709290, PMID:24662565, PMID:25118933, PMID:25094062). Its activity is tuned by phosphorylation: PINK1/p38- and Cdk5-dependent phosphorylation near S400 promotes stress resistance, whereas Akt phosphorylation at S212 attenuates protease activity and pro-apoptotic function (PMID:17906618, PMID:17311912, PMID:21701498). Loss of HTRA2 protease activity causes parkinsonian neurodegeneration, mitochondrial dysfunction, mtDNA damage, and accelerated aging in mice, and biallelic loss-of-function mutations cause a severe human infantile neurodegeneration with 3-methylglutaconic aciduria (PMID:14534547, PMID:15509788, PMID:22976834, PMID:27208207).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2001 High

    Established HTRA2 as a dual pro-apoptotic factor that both antagonizes IAPs through an exposed N-terminal motif and kills via intrinsic protease activity, defining its core role in caspase regulation.

    Evidence BIR3 affinity purification, mass spectrometry, reciprocal Co-IP, RNAi, and protease-dead mutant cell death assays across concurrent studies

    PMID:11602612 PMID:11604410 PMID:11606597

    Open questions at the time
    • Did not resolve how processing exposes the motif
    • In vivo physiological role not yet tested
    • Native substrates of the protease activity unknown
  2. 2002 High

    Showed that HTRA2 assembles into a homotrimer required for both protease and pro-apoptotic function, linking quaternary structure to activity.

    Evidence 2.0 Å X-ray crystallography with monomeric mutants in cell death assays

    PMID:11967569

    Open questions at the time
    • PDZ-protease allosteric coupling not defined
    • Did not capture activated conformation
    • Alternate oligomeric states not detected
  3. 2003 High

    Distinguished HTRA2 from Smac/DIABLO by demonstrating catalytic, irreversible cleavage of IAPs and defined how PDZ engagement and autocatalytic processing switch and amplify activity.

    Evidence In vitro cleavage assays, RNAi, peptide-library substrate/PDZ mapping, autocatalysis reconstitution with N-terminal sequencing

    PMID:12815069 PMID:12835328 PMID:14512424 PMID:15201285

    Open questions at the time
    • Full physiological substrate repertoire not enumerated
    • Quantitative contribution of catalytic vs binding modes in vivo unclear
  4. 2003 High

    Provided the first in vivo evidence that HTRA2 protease activity, not its IAP-binding function, is essential, by showing a protease-inactivating mutation causes neurodegeneration and lethality.

    Evidence mnd2 mouse genetics with BAC transgene rescue, PDZ-deletion reactivation, and mitochondrial permeability transition assays

    PMID:14534547

    Open questions at the time
    • Critical degradation substrates underlying neurodegeneration not identified
    • Mechanism linking protease loss to permeability transition unclear
  5. 2004 High

    Confirmed via knockout that the protease function rather than the Smac-like IAP antagonism drives the parkinsonian phenotype in vivo, redirecting the field toward HTRA2's quality-control role.

    Evidence Prss25 knockout and Prss25/Smac double knockout with histology and behavioral phenotyping

    PMID:15509788

    Open questions at the time
    • Substrates whose accumulation causes striatal loss not defined
    • Relationship to apoptosis-independent neurodegeneration unresolved
  6. 2004 Medium

    Identified the first physiological substrates and activating ligands, including HAX-1, APP, and PED/PEA-15, and showed PDZ engagement by presenilin-1 activates the enzyme analogously to bacterial DegS.

    Evidence Yeast two-hybrid, in vitro cleavage, Co-IP, inhibitor (ucf-101) studies, and PS1 deletion-mutant cellular assays

    PMID:15294909 PMID:15328349 PMID:15371414

    Open questions at the time
    • Substrate cleavage to physiological outcome not always linked
    • Single-lab substrate validations
  7. 2005 Medium

    Connected HTRA2 to additional partners (Apollon, WARTS/LATS1) revealing reciprocal regulation and cell-cycle control, and identified Parkinson's-associated mutations that impair protease activation.

    Evidence In vitro cleavage and ubiquitination assays, Co-IP, RNAi, cell cycle analysis, and patient mutation screening with protease assays

    PMID:15781261 PMID:15961413 PMID:16007220 PMID:17130845

    Open questions at the time
    • Disease causality of G399S/A141S contested by later genetics
    • Reciprocal regulation stoichiometry undefined
  8. 2006 Medium

    Broadened the substrate and process scope by linking HTRA2 to anoikis, APP processing, and a proteome-wide cytoskeletal substrate preference.

    Evidence Subcellular fractionation with Ras/Bcl-XL/Bak manipulation, in vitro/in vivo APP cleavage with mnd2 validation, and COFRADIC N-terminal proteomics

    PMID:16461771 PMID:16968707 PMID:17266347

    Open questions at the time
    • Functional significance of many proteomic substrates untested
    • Physiological vs apoptotic substrate sets not separated
  9. 2007 High

    Established post-translational control of HTRA2 by PINK1/p38 and Akt phosphorylation, linking it to Parkinson's disease signaling and showing kinases bidirectionally tune protease activity and mitochondrial release.

    Evidence Co-IP, in vitro kinase assays, phosphosite mutagenesis (S212), PD patient brain tissue, and pathway inhibition

    PMID:17311912 PMID:17906618

    Open questions at the time
    • Direct kinase for the PINK1-dependent site not fully defined
    • Crosstalk between S212 and S400 phosphorylation unknown
  10. 2007 High

    Defined the PDZ domain as a promiscuous sensor of exposed hydrophobic sequences, providing a structural basis for substrate selection of misfolded proteins, and extended HTRA2 function to ER-associated APP degradation and GRIM-19-dependent IAP destruction.

    Evidence PDZ-ligand crystallography with peptide libraries and alanine scanning, Y2H/Co-IP for APP and GRIM-19, and KO-cell analyses

    PMID:17297443 PMID:17656586 PMID:17684015

    Open questions at the time
    • How promiscuous PDZ recognition achieves substrate specificity in vivo unclear
    • Extra-mitochondrial ER pool not fully characterized
  11. 2008 Medium

    Tested the genetic relationship between HTRA2 and the PINK1/Parkin pathway, yielding conflicting placements and identifying Mpv17l as a PDZ-binding activator regulating mitochondrial ROS.

    Evidence Drosophila epistasis (eye and loss-of-function) and direct Co-IP with ROS/membrane-potential assays for Mpv17l

    PMID:18772386 PMID:19048081 PMID:19118185

    Open questions at the time
    • Conflicting pathway positioning relative to pink1 unresolved
    • Species differences between fly and mammal not reconciled
  12. 2008 Medium

    Extended HTRA2 effector function to caspase-independent death contexts including viral infection and p73-dependent transcriptional apoptosis.

    Evidence Active vs catalytic-mutant overexpression with protease inhibitors and vMIA (CMV), and in vitro p73α cleavage with reporter assays

    PMID:18259191 PMID:18769594

    Open questions at the time
    • Endogenous relevance of p73 cleavage uncertain
    • Single-lab mechanistic claims
  13. 2010 High

    Consolidated HTRA2's role in mitochondrial morphology, autophagy, and transcriptional control through cleavage of OPA1-regulatory targets, HAX-1/Beclin-1 signaling, WT1, and RIP1.

    Evidence Co-IP, in vitro cleavage with site mapping, KO/RNAi cells, ChIP, autophagy flux assays, and mnd2 tissue analysis

    PMID:20064504 PMID:20122399 PMID:20125124 PMID:20467442

    Open questions at the time
    • Direct vs indirect effects on OPA1 not fully separated
    • Balance between apoptotic and homeostatic cleavage events unclear
  14. 2011 High

    Identified Cdk5 as a p38-dependent kinase phosphorylating HTRA2 at S400 to support mitochondrial membrane potential and stress protection.

    Evidence Co-IP, in vitro kinase assay, phosphosite mutagenesis, and membrane-potential assays

    PMID:21701498

    Open questions at the time
    • Substrate-level consequence of S400 phosphorylation undefined
    • Integration with PINK1-dependent phosphorylation unresolved
  15. 2012 High

    Linked HTRA2 protease activity to inflammatory signaling control via MEK1 cleavage, dampening ERK1/2 and NF-κB activation in microglia.

    Evidence RNAi, protease-dead S276C mutant, MEK1 cleavage and signaling assays, and mnd2 brain analysis

    PMID:22912494

    Open questions at the time
    • Contribution to neuroinflammation in disease not quantified
    • Other MAPK-pathway substrates not excluded
  16. 2013 Medium

    Demonstrated that loss of HTRA2 protease activity causes mtDNA damage through elevated ROS and that protease activity protects against necroptosis via UCH-L1 modification.

    Evidence mtDNA conformational assays with KO and targeted rescue, and inhibitor/deletion necroptosis assays with UCH-L1 readout

    PMID:23542127 PMID:24090154

    Open questions at the time
    • Direct vs ROS-mediated effects on mtDNA not separated
    • Mechanism of UCH-L1 monoubiquitination by a protease unexplained
  17. 2014 Medium

    Defined HTRA2 as a central mitochondrial homeostasis regulator through degradation of Mulan, prohibitin, and GSK3β, controlling mitophagy, membrane potential, and PGC-1α-driven biogenesis, while also restraining Ras-driven invasion via β-actin cleavage.

    Evidence In vitro cleavage, Co-IP, KO/knockdown phenotyping with ATP/ROS/membrane assays, rescue experiments, and invasion assays

    PMID:24662565 PMID:24709290 PMID:25094062 PMID:25118933

    Open questions at the time
    • Hierarchy among multiple homeostatic substrates undefined
    • Single-lab in vivo validations
  18. 2018 Medium

    Showed that HTRA2 protease activity restrains NLRP3 and AIM2 inflammasome activation by promoting autophagic clearance of the ASC adaptor, extending its role to innate immune regulation.

    Evidence Ex vivo and in vivo inflammasome challenge in protease-mutant macrophages with autophagy and ASC accumulation assays

    PMID:29855523

    Open questions at the time
    • Direct vs autophagy-mediated control of ASC not fully separated
    • Relevance to human inflammatory disease untested
  19. 2021 High

    Resolved the conformational basis of activity regulation, showing exchange between low-activity trimer and hexamer and cooperative activator-induced domain reorientation that exposes the catalytic center.

    Evidence Methyl-TROSY solution NMR with biochemical activity and substrate-affinity assays

    PMID:33692127

    Open questions at the time
    • Physiological triggers of trimer-hexamer exchange in cells unknown
    • Whether hexamer forms a regulatory reservoir in vivo untested
  20. 2016 High

    Confirmed HTRA2 as the cause of a human Mendelian neurodegenerative disorder and functionally separated its chaperone from protease activities in rescuing patient cells.

    Evidence Whole-exome sequencing and patient fibroblast complementation with WT vs protease-inactive HTRA2

    PMID:27208207

    Open questions at the time
    • Molecular basis of the chaperone-only activity undefined
    • Substrates underlying 3-methylglutaconic aciduria not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HTRA2 selects among its many substrates in distinct physiological versus apoptotic states, and what triggers its conformational and oligomeric transitions inside cells, remains unresolved.
  • No unified model distinguishing homeostatic from apoptotic substrate selection
  • In vivo triggers of trimer-hexamer-activator transitions unknown
  • Chaperone activity mechanism uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016787 hydrolase activity 4 GO:0098772 molecular function regulator activity 4 GO:0044183 protein folding chaperone 1
Localization
GO:0005739 mitochondrion 7 GO:0005829 cytosol 4 GO:0005634 nucleus 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-5357801 Programmed Cell Death 6 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 2
Partners
HAX-1LATS1MPV17LOPA1PARKINPINK1PROHIBITINXIAP

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 HTRA2/Omi is a mitochondrial serine protease that is released from the mitochondrial intermembrane space into the cytosol upon apoptotic stimuli. Upon release, its N-terminal IAP-binding motif (AVPS), exposed after processing of its mitochondrial targeting sequence, directly binds the BIR3 domain of XIAP, disrupting caspase-IAP interactions and promoting caspase-dependent apoptosis. HTRA2 can also induce caspase-independent apoptosis through its intrinsic protease activity. Affinity purification using BIR3 domain, microsequencing, mass spectrometry, Co-IP, cell death assays with wild-type vs protease-dead mutants The Journal of biological chemistry High 11606597
2001 Mature HTRA2/Omi autoprocesses to expose an N-terminal Reaper-like/Smac-like motif. Full-length HTRA2 is localized to mitochondria and fails to interact with XIAP; processed HTRA2 translocates to the cytosol upon apoptotic insult where it interacts with XIAP via this motif. RNA interference knockdown of HTRA2 reduces cell death. Subcellular fractionation, Co-IP, RNAi knockdown, overexpression assays The Journal of biological chemistry High 11602612
2001 HTRA2 binds MIHA/XIAP, MIHB, and baculoviral OpIAP but not survivin. Processed HTRA2 with its N-terminal Grim/Reaper-like motif mediates IAP interaction. Mutation of either the N-terminal alanine (required for IAP interaction) or the catalytic serine reduces pro-apoptotic activity; mutation of both abolishes it entirely. HTRA2 prevents XIAP inhibition of active caspase-3 in vitro. Co-IP, in vitro caspase inhibition assay, site-directed mutagenesis, cell death assays The Journal of biological chemistry High 11604410
2002 Crystal structure of HTRA2/Omi at 2.0 Å reveals a pyramid-shaped homotrimer mediated exclusively by the serine protease domains. The PDZ domain's peptide-binding pocket is buried at the PDZ-protease interface. Monomeric HTRA2 mutants are unable to induce cell death and are deficient in protease activity, establishing that trimerization is required for function. The PDZ domain modulates serine protease activity and cell death activity. X-ray crystallography (2.0 Å), mutational analysis, cell death assays Nature structural biology High 11967569
2003 HTRA2/Omi directly and catalytically cleaves IAPs (including c-IAP1) in vitro. The cleavage efficiency is determined by its N-terminal IAP-binding motif (AVPS). Unlike stoichiometric antagonism by Smac/DIABLO, HTRA2 cleavage of IAPs is catalytic and irreversible, more efficiently inactivating IAPs and promoting caspase activity. Endogenous HTRA2 suppression by RNAi abolishes c-IAP1 cleavage and desensitizes cells to TRAIL-induced apoptosis. In vitro cleavage assay, RNAi knockdown, cell death assays (TRAIL stimulation) Genes & development High 12815069
2003 IAP family members are direct substrates of HTRA2/Omi serine protease activity. Ectopic expression of catalytically active but not active-site mutant HTRA2 induces potent caspase activation; increased HTRA2 expression accelerates XIAP degradation in cells; HTRA2 RNAi has the opposite effect. Demonstrates that IAP proteolysis is a mechanism by which mitochondrially released HTRA2 activates caspases. In vitro protease degradation assay, overexpression, RNAi, Western blot of XIAP levels The Journal of biological chemistry High 12835328
2003 Peptide library screening determined the optimal substrate cleavage sequence for HTRA2 serine protease and the preferred PDZ-domain binding sequence. PDZ domain engagement by a binding partner suppresses protease activity in its unengaged state but engagement (including by XIAP's Reaper motif) markedly increases proteolytic activity, suggesting that IAP binding can switch HTRA2 from caspase inhibition to serine protease activation. Heat shock treatment also activates HTRA2 protease activity. Peptide library screening, in vitro protease activity assays, PDZ binding assays The Journal of biological chemistry High 14512424
2003 Loss of HTRA2 protease activity in mnd2 mice (Ser276Cys missense mutation in the protease domain) causes neurodegeneration, muscle wasting, and juvenile lethality. Deletion of the PDZ domain partially restores protease activity to the inactive Ser276Cys mutant, indicating the mutation impairs substrate access or active-site binding. Loss of HTRA2 activity increases mitochondrial permeability transition susceptibility and stress-induced cell death in MEFs. Mouse genetics (mnd2 mutant), BAC transgene rescue, in vitro protease assay, PDZ deletion mutant, mitochondrial permeability transition assay Nature High 14534547
2004 Targeted deletion of HTRA2/Omi in mice (Prss25 knockout) causes striatal neuronal loss and a parkinsonian neurodegenerative phenotype leading to death ~30 days after birth, without evidence of reduced cell death. Simultaneous deletion of Smac/DIABLO does not alter the phenotype, indicating the protease function (not IAP-binding motif) is critical in vivo. Gene knockout (Prss25), double knockout (Prss25 + Smac/Diablo), histology, behavioral phenotyping Molecular and cellular biology High 15509788
2004 HAX-1, a mitochondrial anti-apoptotic protein, is a specific substrate of HTRA2/Omi. HAX-1 is cleaved by HTRA2 both in vitro and in vivo upon apoptotic stimulation, and HAX-1 degradation begins while HTRA2 is still confined in the mitochondria (prior to its cytosolic release). Specific HTRA2 inhibitor (ucf-101) blocks HAX-1 degradation and reduces cell death. Cleavage is absent in mnd2 cells with protease-dead HTRA2. Yeast two-hybrid, in vitro cleavage assay, Co-IP, subcellular fractionation, pharmacological inhibition, mnd2 cell line The Journal of biological chemistry High 15371414
2004 The C-terminal cytoplasmic tail peptide of presenilin-1 (PS1) directly interacts with the PDZ domain of HTRA2/Omi and dramatically increases its proteolytic activity toward IAPs and beta-casein. Ectopic expression of full-length PS1 but not PS1 lacking the C-terminal PDZ-binding motif potentiates HTRA2-induced cell death. This PDZ-domain mediated activation mechanism is analogous to bacterial DegS activation by outer-membrane porins. Direct in vitro protease activity assay, PDZ binding, Co-IP, overexpression of PS1 deletion mutants, cell death assay The Journal of biological chemistry High 15294909
2004 HTRA2/Omi is autocatalytically processed via an intermolecular mechanism. The autocatalytic cleavage site is on the carboxyl side of Ala133, generating a 36-kDa form that exposes the IAP-binding motif. This processed form is required for cytochrome c-dependent caspase activation and XIAP neutralization. Autocatalytic processing is essential for HTRA2-mediated apoptotic cell death. In vitro mixing of active and inactive (S306A) HTRA2, N-terminal amino acid sequencing, mutational analysis, caspase activation assay The Journal of biological chemistry High 15201285
2005 HTRA2 directly cleaves Apollon/BRUCE (a giant IAP protein) via its serine protease activity, while reciprocally Apollon ubiquitylates HTRA2 (which binds Apollon via its IAP-binding motif) to facilitate proteasomal degradation of HTRA2. In Apollon-deficient cells, catalytically inactive HTRA2 with intact IAP-binding motif is sufficient to induce apoptosis. In vitro cleavage assay, co-immunoprecipitation, ubiquitination assay, cell death assays in Apollon-deficient cells Biochemical and biophysical research communications Medium 15781261
2005 G399S and A141S mutations in HTRA2/Omi found in Parkinson's disease patients result in defective activation of HTRA2 protease activity. S399 mutant HTRA2 causes mitochondrial dysfunction and altered mitochondrial morphology in stably transfected cells, and cells overexpressing S399 mutant HTRA2 are more susceptible to stress-induced cell death. Patient mutation screening, in vitro protease activity assay, stable cell transfection, mitochondrial morphology analysis, cell death assay Human molecular genetics High 15961413
2006 APP (amyloid precursor protein) is a direct cleavage substrate of HTRA2 serine protease both in vitro and in vivo. HTRA2-mediated cleavage produces a C161 fragment (amino acids 535-695 of APP695). APP and HTRA2 co-localize in mitochondria where cleavage occurs under normal conditions. The C161 fragment is substantially decreased in mnd2 mice lacking HTRA2 protease activity. In vitro cleavage assay, N-terminal amino acid sequencing of cleavage product, immunofluorescence, subcellular fractionation, mnd2 mouse tissue analysis The Journal of biological chemistry High 16968707
2006 HTRA2/Omi is an inducer of anoikis in intestinal epithelial cells. Release of HTRA2 from mitochondria is driven by detachment-induced down-regulation of Bcl-XL. Oncogenic Ras inhibits anoikis by preventing HTRA2 release, an effect requiring Ras-induced downregulation of Bak and dependent on PI3-kinase. Subcellular fractionation, cell detachment assays, genetic manipulation (Ras expression, Bcl-XL, Bak), pharmacological inhibition of PI3K The Journal of biological chemistry Medium 16461771
2007 HTRA2/Omi interacts with PINK1 (a mitochondrial protein kinase linked to PARK6 Parkinson's disease). HTRA2 is phosphorylated in a PINK1-dependent manner on a residue adjacent to a PD mutation site (near S400) via the p38 stress-sensing pathway. HTRA2 phosphorylation is decreased in brains of PINK1-mutant PD patients. PINK1-dependent phosphorylation modulates HTRA2 proteolytic activity and promotes resistance to mitochondrial stress. Co-immunoprecipitation (HTRA2-PINK1 interaction), phosphorylation assay, brain tissue analysis from PD patients, p38 pathway pharmacological inhibition Nature cell biology High 17906618
2007 HTRA2/Omi regulates APP metabolism through ER-associated degradation (ERAD). HtrA2 binds the N-terminal cysteine-rich region of APP (identified by Y2H) and co-immunoprecipitates exclusively with immature APP. A subpopulation of HTRA2 localizes to the cytosolic side of the ER membrane. In HtrA2-deficient cells, APP holoprotein accumulates in the early secretory pathway with elevated APP C-terminal fragments and increased Abeta secretion. Yeast two-hybrid, Co-IP from cell lysates and mouse brain, subcellular fractionation, HtrA2-null cell analysis The Journal of biological chemistry Medium 17684015
2007 Proteome-wide screen using COFRADIC identified 15 HTRA2 substrates in Jurkat cell lysates. HTRA2 shows a narrow cleavage site preference and cytoskeletal proteins are prime targets. Selected substrates were validated by in vitro cleavage of recombinant proteins or with Jurkat cell lysates. Mass spectrometry-based COFRADIC N-terminal proteomics, in vitro cleavage validation with recombinant proteins Journal of proteome research Medium 17266347
2007 Akt1 and Akt2 phosphorylate HTRA2/Omi at serine 212 in vivo and in vitro, attenuating its serine protease activity and pro-apoptotic function. S212A mutant retains protease activity and induces more apoptosis; S212D phosphomimetic mutant loses protease activity and fails to induce cell death. Phosphorylated HTRA2 fails to cleave XIAP without disrupting complex formation. Akt also inhibits HTRA2 release from mitochondria. In vitro kinase assay, site-directed mutagenesis (S212A, S212D), in vitro protease activity assay, cell death assays, subcellular fractionation The Journal of biological chemistry High 17311912
2007 GRIM-19 physically interacts with HTRA2 serine protease. In the presence of GRIM-19, HTRA2-driven destruction of XIAP is augmented, promoting IFN/retinoic acid-induced cell death. This interaction is disrupted by the HHV-8 oncoprotein vIRF1, conferring resistance to cell death. Yeast two-hybrid, Co-IP, XIAP degradation assay, cell death assay, vIRF1 expression Oncogene Medium 17297443
2007 Structural and functional analysis of the HTRA2 PDZ domain using peptide libraries and X-ray crystallography shows that the PDZ domain recognizes both C-terminal and internal stretches of extended, hydrophobic polypeptides. High-affinity recognition requires contacts with up to five hydrophobic side chains; no single residue type is absolutely required, indicating the PDZ domain is promiscuous and adapted to recognize misfolded proteins with exposed hydrophobic sequences. X-ray crystallography of PDZ-ligand complexes, peptide library affinity assays, alanine-scanning mutagenesis Protein science High 17656586
2008 In Drosophila epistasis experiments, omi/htrA2 acts genetically downstream of pink1 but functions independently of Parkin. Rhomboid-7, a mitochondrial intramembrane protease, acts upstream and is required to cleave the precursor forms of both Pink1 and Omi, placing regulated intramembrane proteolysis upstream of this pathway. Drosophila ectopic eye expression epistasis assay, genetic double mutant analysis Disease models & mechanisms Medium 19048081
2008 Loss-of-function analysis in Drosophila shows that Omi/HtrA2 null mutants do not exhibit mitochondrial morphological defects (unlike pink1 or parkin null mutants). Extensive genetic interaction studies do not support a model in which Omi/HtrA2 functions in the same pathway as pink1 for regulation of mitochondrial integrity. G399S retains significant Omi/HtrA2 function compared to protease-compromised versions. Drosophila loss-of-function genetics, genetic interaction studies, mitochondrial morphology analysis The Journal of neuroscience Medium 19118185
2008 Mpv17l directly interacts with HTRA2 in mitochondria via the PDZ domain and induces HTRA2 protease activation. HTRA2 inhibits mitochondrial superoxide generation, stabilizes mitochondrial membrane potential, and prevents apoptosis at baseline and in response to mitochondrial stress inducers. Oxidative stress-induced downregulation of Mpv17l occurs in renal injury models. Co-IP (direct interaction), protease activity assay after Mpv17l interaction, mitochondrial ROS measurement, membrane potential assay Proceedings of the National Academy of Sciences of the United States of America High 18772386
2008 HtrA2/Omi initiates caspase-independent death during cytomegalovirus infection. Infected cells become susceptible to death as mitochondrial HTRA2 levels increase. Experimental overexpression of catalytically active (but not catalytic-site mutant) HTRA2 sensitizes infected cells to death that can be blocked by vMIA (viral mitochondria-localized inhibitor of apoptosis) or protease inhibitors. Uninfected cells are completely resistant to HTRA2-induced death. Overexpression of wild-type vs catalytic mutant HTRA2, pharmacological serine protease inhibitors, vMIA expression, cell death assays PLoS pathogens Medium 18769594
2009 HtrA2 cleaves Parkin and irreversibly inactivates its E3 ubiquitin ligase activity. HtrA2 co-localizes with Parkin in the cytosol upon cellular stress-induced mitochondrial release. Endogenous Parkin levels are significantly decreased in HtrA2+/+ MEFs compared to HtrA2−/− MEFs under stress. HtrA2-mediated Parkin cleavage disrupts Parkin-mediated synphilin-1 ubiquitination and autoubiquitination. Co-IP, in vitro cleavage assay, ubiquitination assay, HtrA2 KO vs WT MEF comparison, immunofluorescence co-localization Biochemical and biophysical research communications Medium 19631192
2010 The Wilms' tumor suppressor WT1 is a direct substrate of HTRA2 serine protease. HtrA2 binds WT1 and cleaves it at multiple sites following cytotoxic drug treatment. Ablation of HtrA2 activity (by chemical inhibitor or siRNA) prevents WT1 proteolysis under apoptotic conditions. Apoptosis-dependent WT1 cleavage is defective in HtrA2 knockout cells. WT1 proteolysis by HtrA2 removes WT1 from gene promoters, altering gene regulation to enhance apoptosis. Co-IP, in vitro cleavage assay, siRNA knockdown, HtrA2 KO cells, chromatin immunoprecipitation for WT1 promoter binding Molecular cell High 20122399
2010 HTRA2/Omi directly interacts with OPA1 (a mitochondrial fusion factor) by co-immunoprecipitation. Loss of HTRA2 function causes elongated mitochondria, increased soluble OPA1, and abnormal cristae structure. Complementation with wild-type but not protease mutant (S306A) HTRA2 reverses mitochondrial elongation and OPA1 alterations, demonstrating that HTRA2 protease activity modulates mitochondrial morphology via OPA1 regulation. Co-IP, live cell imaging, electron microscopy, Western blot of OPA1 isoforms, complementation with WT vs protease mutant Experimental cell research High 20064504
2010 HTRA2/Omi activates autophagy by digesting HAX-1, a Bcl-2-related protein that represses autophagy in a Beclin-1-dependent pathway. HTRA2-induced autophagy facilitates degradation of neurodegenerative proteins (A53T α-synuclein, polyglutamine-expanded huntingtin, p62). Knockdown of HTRA2 decreases basal autophagy and increases autophagy substrate levels. S276C protease-defective Omi mutant fails to regulate autophagy; mnd2 mouse brains show increased autophagy substrates. In vitro and cellular HAX-1 cleavage, Beclin-1 interaction assay, autophagy flux assays, RNAi, mnd2 mouse tissue analysis Cell death and differentiation Medium 20467442
2010 HtrA2/Omi cleaves RIP1 during growth factor withdrawal-induced caspase-independent cell death. Recombinant HtrA2/Omi efficiently cleaves mouse RIP1 in vitro generating a 25-kDa C-terminal fragment. The cleavage site maps to the intermediate domain of RIP1. HtrA2-generated RIP1 fragments are impaired in activating NF-κB, JNK, and p38 MAPK. RNAi knockdown of HtrA2 protects against IL-3 withdrawal-induced death in the presence of zVAD-fmk. siRNA knockdown, recombinant in vitro cleavage assay, cleavage site mapping, NF-κB/JNK/p38 activity assays Cell research High 20125124
2011 Cyclin-dependent kinase 5 (Cdk5) phosphorylates HTRA2 at S400 in a p38-dependent manner. HTRA2 and Cdk5 interact in human and mouse cell lines and brain. Phosphorylation of HTRA2 at S400 is involved in maintaining mitochondrial membrane potential under stress conditions and is important for mitochondrial function, conferring protection against cellular stress. Co-IP (HTRA2-Cdk5 interaction), in vitro kinase assay, phosphorylation site mutagenesis, mitochondrial membrane potential assay Cell death and differentiation High 21701498
2012 Omi/HtrA2 cleaves MEK1 (mitogen-activated protein kinase kinase 1) to suppress ERK1/2 activation in microglia. Knockdown of Omi leads to MEK1 accumulation, ERK1/2 activation, IκBα degradation, NF-κB activation, and expression of inflammatory molecules (TNF-α, iNOS). The protease-deficient S276C Omi mutant does not cleave MEK1 or affect ERK1/2 activation. mnd2 mouse brains show increased inflammatory gene expression. RNAi knockdown, protease-dead mutant expression, MEK1 cleavage assay, ERK1/2 and NF-κB activity assays, mnd2 mouse brain analysis Science signaling High 22912494
2013 HtrA2/Omi deficiency causes accumulation of nicked and mutated mitochondrial DNA through reactive oxygen species generated by loss of HTRA2 protease activity. Overexpression of HTRA2 with protease activity targeted to mitochondria restores mtDNA conformational stability in HTRA2−/− MEF cells. Agarose gel electrophoresis of mtDNA, PicoGreen intercalation assay, long-range PCR, HTRA2 KO cells, targeted re-expression Biochimica et biophysica acta Medium 23542127
2013 Pharmacological or genetic deletion of HTRA2/Omi protects cells from TNF-induced necroptosis. During TNF-induced necroptosis, HtrA2/Omi induces monoubiquitination of UCH-L1 (rather than cleaving it as in apoptosis), activating UCH-L1 which mediates caspase-independent cell death. Pharmacological serine protease inhibitor screen, HTRA2 genetic deletion, cell death assays, Western blot for UCH-L1 modification Cell communication and signaling Medium 24090154
2014 Mulan E3 ubiquitin ligase is a specific substrate of HTRA2/Omi protease. During H2O2 exposure, HTRA2 degrades Mulan; this regulation is lost in mnd2 cells. Mulan accumulation in mnd2 mice and HTRA2−/− MEFs causes decreased mitofusin 2 (Mfn2) protein levels and increased mitophagy. In vitro cleavage assay, mnd2 tissue and KO MEF analysis, Western blot for Mulan and Mfn2, mitophagy assay Biochimica et biophysica acta Medium 24709290
2014 p53 induces activation of HTRA2 by promoting p38 MAPK translocation into mitochondria and inducing HTRA2 phosphorylation. Concurrently, oncogenic Ras induces mitochondrial fragmentation causing HTRA2 release into cytosol. Phosphorylated HTRA2 cleaves β-actin in the cytosol, decreasing F-actin and downregulating p130Cas-mediated lamellipodia formation, preventing Ras-driven cell invasion. Subcellular fractionation, p38 inhibitors, HTRA2 phosphorylation assay, in vitro β-actin cleavage assay, lamellipodia/invasion assays, p53 manipulation The Journal of cell biology Medium 24662565
2014 Omi/HtrA2 protease cleaves GSK3β, preventing its promotion of PGC-1α degradation, thereby regulating PGC-1α and mitochondrial biogenesis. In mnd2 mice, GSK3β is increased and PGC-1α is decreased. GSK3β inhibition or PGC-1α overexpression restores mitochondrial biogenesis in mnd2 mice. In vitro cleavage assay for GSK3β, mnd2 mouse tissue analysis, pharmacological GSK3β inhibition, PGC-1α overexpression, movement ability assessment Cell death & disease Medium 25118933
2014 Prohibitin (PHB) interacts with and is directly cleaved by HTRA2. LONP1 and PHB are overexpressed in HTRA2−/− MEF cells and HTRA2-knockdown cells. HTRA2 deficiency causes decreased mitochondrial membrane potential, decreased intracellular ATP, and increased ROS generation, establishing HTRA2 as an upstream regulator of mitochondrial homeostasis. Co-IP (PHB-HTRA2 interaction), in vitro cleavage assay, KO and knockdown cells, ATP luminescence assay, ROS measurement, membrane potential assay Experimental cell research Medium 25094062
2018 HtrA2 protease activity restricts the activation of ASC-dependent NLRP3 and AIM2 inflammasomes. Loss of HtrA2 protease activity results in exacerbated NLRP3 and AIM2 inflammasome responses ex vivo and in vivo. Mechanistically, HtrA2 regulates autophagy and prevents prolonged accumulation of the inflammasome adaptor ASC, controlling the magnitude and duration of inflammasome signaling. Macrophage ex vivo inflammasome assays, in vivo inflammasome challenge, HtrA2 protease mutant analysis, autophagy assays, ASC accumulation assay Scientific reports Medium 29855523
2021 Solution NMR (methyl-TROSY) reveals that HtrA2 exchanges between a trimeric and a previously unobserved hexameric conformation. The hexamer shows much weaker affinity toward substrates. Both trimer and hexamer are substrate-inaccessible explaining low basal activity. Binding of activator peptide to each protomer of the trimer occurs with positive cooperativity and induces intrasubunit domain reorientations that expose the catalytic center, increasing proteolytic activity. HtrA2 activity is thus modulated both by oligomerization and domain reorientation. Methyl-TROSY NMR, biochemical activity assays, substrate affinity measurements Proceedings of the National Academy of Sciences of the United States of America High 33692127
2008 p73α is cleaved in its C-terminal portion by HtrA2 serine protease following apoptotic stimuli. Upon cleavage, HtrA2 accumulates in the nucleus and enables p73 to increase its transactivation activity on the apoptotic gene BAX but not on p21. p73 requires HtrA2 to activate and enhance its apoptotic functions (caspase activation and nuclear fragmentation). In vitro cleavage assay, nuclear fractionation, gene reporter assays (BAX, p21 promoters), cell death assays Cell death and differentiation Medium 18259191
2009 Omi/HtrA2 directly binds to and degrades anti-apoptotic protein ped/pea-15. Binding is induced by UVC exposure and follows HTRA2 mitochondrial release into cytoplasm. Degradation of ped/pea-15 was demonstrated in vitro with recombinant HTRA2. The HTRA2-specific inhibitor ucf-101 prevents ped/pea-15 degradation dose-dependently. ped/pea-15 expression blocks HTRA2 co-precipitation with XIAP and caspase-3 activation. Yeast two-hybrid, in vitro pulldown with recombinant protein, Co-IP, in vitro cleavage assay, pharmacological inhibition The Journal of biological chemistry Medium 15328349
2005 WARTS kinase (LATS1) binds via its C-terminus to the PDZ domain of HTRA2 and enhances HTRA2 protease activity both in vivo and in vitro. Depletion of WARTS inhibits HTRA2-mediated cell death; overexpression promotes it. WARTS is itself a substrate for HTRA2 and is proteolysed by active HTRA2 in a PDZ-domain-interaction-dependent manner. HTRA2-mediated processing of WARTS negatively regulates G1/S cell cycle progression. Co-IP, in vitro protease activity assay, yeast two-hybrid, RNAi depletion, cell death assays, cell cycle analysis Oncogene / Oncogene Medium 16007220 17130845
2012 Loss of HTRA2 activity in non-neuronal tissues causes accelerated aging phenotypes (premature weight loss, hair loss, reduced fertility, spine curvature, heart enlargement, increased autophagy) and elevated clonally expanded mtDNA deletions, providing direct genetic evidence linking mitochondrial protein quality control to mtDNA deletions and aging. CNS-targeted HTRA2 transgenic rescue of mnd2 mice, phenotypic analysis, mtDNA deletion analysis (long-range PCR, clonal expansion) Cell death and differentiation Medium 22976834
2016 Human patients with biallelic loss-of-function mutations in HTRA2 (missplicing and 5-bp deletion causing complete protein absence) develop severe infantile neurodegeneration with 3-methylglutaconic aciduria, abnormal mitochondria, and increased sensitivity to apoptosis. Expression of proteolytically active but not inactive HtrA2 restored cell growth, while both restored apoptotic resistance, distinguishing chaperone from protease functions. Whole-exome sequencing, patient fibroblast complementation with WT vs protease-inactive HTRA2, cell growth and apoptosis assays Journal of medical genetics High 27208207

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. The Journal of biological chemistry 576 11606597
2005 Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Human molecular genetics 436 15961413
2001 The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. The Journal of biological chemistry 435 11602612
2001 HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. The Journal of biological chemistry 435 11604410
2007 The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. Nature cell biology 385 17906618
2004 Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. Molecular and cellular biology 325 15509788
2003 Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice. Nature 304 14534547
2003 Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis. Genes & development 250 12815069
2002 Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi. Nature structural biology 236 11967569
2003 Inhibitor of apoptosis proteins are substrates for the mitochondrial serine protease Omi/HtrA2. The Journal of biological chemistry 155 12835328
2004 Regulation of HAX-1 anti-apoptotic protein by Omi/HtrA2 protease during cell death. The Journal of biological chemistry 152 15371414
2004 Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways. Cell death and differentiation 149 14605674
2008 Rhomboid-7 and HtrA2/Omi act in a common pathway with the Parkinson's disease factors Pink1 and Parkin. Disease models & mechanisms 147 19048081
2003 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. Cancer research 122 12670894
2003 Binding specificity and regulation of the serine protease and PDZ domains of HtrA2/Omi. The Journal of biological chemistry 113 14512424
2006 The inhibitor-of-apoptosis protein Bir1p protects against apoptosis in S. cerevisiae and is a substrate for the yeast homologue of Omi/HtrA2. Journal of cell science 108 16608876
2007 S100A8/9 induces cell death via a novel, RAGE-independent pathway that involves selective release of Smac/DIABLO and Omi/HtrA2. Biochimica et biophysica acta 107 18060880
2003 Characterization of a novel and specific inhibitor for the pro-apoptotic protease Omi/HtrA2. The Journal of biological chemistry 102 12529364
2007 Proteome-wide Identification of HtrA2/Omi Substrates. Journal of proteome research 98 17266347
2013 Alternative germ cell death pathway in Drosophila involves HtrA2/Omi, lysosomes, and a caspase-9 counterpart. Developmental cell 91 23523076
2006 Beta-amyloid precursor protein is a direct cleavage target of HtrA2 serine protease. Implications for the physiological function of HtrA2 in the mitochondria. The Journal of biological chemistry 86 16968707
2009 Mitochondrial quality control: insights on how Parkinson's disease related genes PINK1, parkin, and Omi/HtrA2 interact to maintain mitochondrial homeostasis. Journal of bioenergetics and biomembranes 85 20012177
2004 Role of Omi/HtrA2 in apoptotic cell death after myocardial ischemia and reperfusion. Circulation 85 15611365
2010 Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases. Cell death and differentiation 79 20467442
2008 Mpv17l protects against mitochondrial oxidative stress and apoptosis by activation of Omi/HtrA2 protease. Proceedings of the National Academy of Sciences of the United States of America 78 18772386
2004 The C-terminal tail of presenilin regulates Omi/HtrA2 protease activity. The Journal of biological chemistry 73 15294909
2008 Loss-of-function analysis suggests that Omi/HtrA2 is not an essential component of the PINK1/PARKIN pathway in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience 72 19118185
2004 Omi/HtrA2 promotes cell death by binding and degrading the anti-apoptotic protein ped/pea-15. The Journal of biological chemistry 72 15328349
1997 Molecular cloning of htra2-beta-1 and htra2-beta-2, two human homologs of tra-2 generated by alternative splicing. DNA and cell biology 72 9212162
2012 Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging. Cell death and differentiation 70 22976834
2007 HtrA2 regulates beta-amyloid precursor protein (APP) metabolism through endoplasmic reticulum-associated degradation. The Journal of biological chemistry 67 17684015
2010 The Wilms' tumor suppressor protein WT1 is processed by the serine protease HtrA2/Omi. Molecular cell 65 20122399
2004 Omi/HtrA2 protease mediates cisplatin-induced cell death in renal cells. American journal of physiology. Renal physiology 63 15454391
2017 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 : international journal of experimental cellular physiology, biochemistry, and pharmacology 60 29241219
2010 Modulation of mitochondrial function and morphology by interaction of Omi/HtrA2 with the mitochondrial fusion factor OPA1. Experimental cell research 60 20064504
2014 Inactivation of Omi/HtrA2 protease leads to the deregulation of mitochondrial Mulan E3 ubiquitin ligase and increased mitophagy. Biochimica et biophysica acta 57 24709290
2008 Genetic variation of Omi/HtrA2 and Parkinson's disease. Parkinsonism & related disorders 57 18790661
2013 The proteases HtrA2/Omi and UCH-L1 regulate TNF-induced necroptosis. Cell communication and signaling : CCS 56 24090154
2006 Inhibition of HtrA2/Omi ameliorates heart dysfunction following ischemia/reperfusion injury in rat heart in vivo. European journal of pharmacology 56 17182030
2008 Changes in mRNA and protein levels of human HtrA1, HtrA2 and HtrA3 in ovarian cancer. Clinical biochemistry 55 18241672
2006 The serine protease Omi/HtrA2 is involved in XIAP cleavage and in neuronal cell death following focal cerebral ischemia/reperfusion. Neurochemistry international 54 16978742
2009 A large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson's disease. Neurobiology of aging 53 20036034
2013 HtrA2/Omi deficiency causes damage and mutation of mitochondrial DNA. Biochimica et biophysica acta 52 23542127
2014 The protease Omi regulates mitochondrial biogenesis through the GSK3β/PGC-1α pathway. Cell death & disease 51 25118933
2007 Structural and functional analysis of the ligand specificity of the HtrA2/Omi PDZ domain. Protein science : a publication of the Protein Society 51 17656586
2009 Expression of human HtrA1, HtrA2, HtrA3 and TGF-beta1 genes in primary endometrial cancer. Oncology reports 50 19424634
2000 Expression, purification, and functional analysis of the human serine protease HtrA2. Protein expression and purification 49 10873535
2008 HtrA2/Omi terminates cytomegalovirus infection and is controlled by the viral mitochondrial inhibitor of apoptosis (vMIA). PLoS pathogens 47 18769594
2011 Idebenone and resveratrol extend lifespan and improve motor function of HtrA2 knockout mice. PloS one 45 22205977
2021 Prevention of acquired sensorineural hearing loss in mice by in vivo Htra2 gene editing. Genome biology 44 33752742
2011 Novel variant Pro143Ala in HTRA2 contributes to Parkinson's disease by inducing hyperphosphorylation of HTRA2 protein in mitochondria. Human genetics 44 21701785
2008 Participation of Omi Htra2 serine-protease activity in the apoptosis induced by cisplatin on SW480 colon cancer cells. Journal of chemotherapy (Florence, Italy) 44 18606591
2008 Accumulation of HtrA2/Omi in neuronal and glial inclusions in brains with alpha-synucleinopathies. Journal of neuropathology and experimental neurology 44 18800009
2005 HtrA2 cleaves Apollon and induces cell death by IAP-binding motif in Apollon-deficient cells. Biochemical and biophysical research communications 44 15781261
2008 Activation of HtrA2, a mitochondrial serine protease mediates apoptosis: current knowledge on HtrA2 mediated myocardial ischemia/reperfusion injury. Cardiovascular therapeutics 43 18786092
2006 Oncogenic Ras inhibits anoikis of intestinal epithelial cells by preventing the release of a mitochondrial pro-apoptotic protein Omi/HtrA2 into the cytoplasm. The Journal of biological chemistry 42 16461771
2005 The tumor suppressor WARTS activates the Omi / HtrA2-dependent pathway of cell death. Oncogene 40 16007220
2004 Autocatalytic processing of HtrA2/Omi is essential for induction of caspase-dependent cell death through antagonizing XIAP. The Journal of biological chemistry 40 15201285
2014 p53-mediated activation of the mitochondrial protease HtrA2/Omi prevents cell invasion. The Journal of cell biology 39 24662565
2008 Tunicamycin-induced ER stress upregulates the expression of mitochondrial HtrA2 and promotes apoptosis through the cytosolic release of HtrA2. Journal of microbiology and biotechnology 39 18600068
2005 Regulation of HtrA2/Omi by X-linked inhibitor of apoptosis protein in chemoresistance in human ovarian cancer cells. Gynecologic oncology 39 15863139
2011 Phosphorylation of HtrA2 by cyclin-dependent kinase-5 is important for mitochondrial function. Cell death and differentiation 37 21701498
2009 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 37 19502560
2016 Cardiac Specific Overexpression of Mitochondrial Omi/HtrA2 Induces Myocardial Apoptosis and Cardiac Dysfunction. Scientific reports 36 27924873
2009 Glycogen synthase kinase-3 and Omi/HtrA2 induce annexin A2 cleavage followed by cell cycle inhibition and apoptosis. Molecular biology of the cell 36 19656851
2007 GRIM-19 associates with the serine protease HtrA2 for promoting cell death. Oncogene 36 17297443
2003 HtrA2/Omi, a sheep in wolf's clothing. Cell 36 14636553
2012 A novel role for the mitochondrial HTRA2/OMI protease in aging. Autophagy 35 23242108
2011 Melatonin protects against rotenone-induced cell injury via inhibition of Omi and Bax-mediated autophagy in Hela cells. Journal of pineal research 35 21883444
2010 The induction of reactive oxygen species and loss of mitochondrial Omi/HtrA2 is associated with S-nitrosoglutathione-induced apoptosis in human endothelial cells. Toxicology and applied pharmacology 35 20153346
2007 Akt attenuation of the serine protease activity of HtrA2/Omi through phosphorylation of serine 212. The Journal of biological chemistry 35 17311912
2007 Evolution of mitochondrial cell death pathway: Proapoptotic role of HtrA2/Omi in Drosophila. Biochemical and biophysical research communications 33 17397804
2006 Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation. Oncogene 32 17130845
2018 Omi/HtrA2 Regulates a Mitochondria-Dependent Apoptotic Pathway in a Murine Model of Septic Encephalopathy. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 31 30286467
2009 Enhanced HtrA2/Omi expression in oxidative injury to retinal pigment epithelial cells and murine models of neurodegeneration. Investigative ophthalmology & visual science 31 19443712
2021 Oligomeric assembly regulating mitochondrial HtrA2 function as examined by methyl-TROSY NMR. Proceedings of the National Academy of Sciences of the United States of America 30 33692127
2019 Omi/HtrA2 Protease Associated Cell Apoptosis Participates in Blood-Brain Barrier Dysfunction. Frontiers in molecular neuroscience 30 30853894
2016 Deficiency of HTRA2/Omi is associated with infantile neurodegeneration and 3-methylglutaconic aciduria. Journal of medical genetics 30 27208207
2015 HNRNP G and HTRA2-BETA1 regulate estrogen receptor alpha expression with potential impact on endometrial cancer. BMC cancer 30 25884434
2012 Variations in the protein level of Omi/HtrA2 in the heart of aged rats may contribute to the increased susceptibility of cardiomyocytes to ischemia/reperfusion injury and cell death : Omi/HtrA2 and aged heart injury. Age (Dordrecht, Netherlands) 30 22535253
2012 Temperature-induced changes of HtrA2(Omi) protease activity and structure. Cell stress & chaperones 30 22851136
2007 Transgenic mice with neuron-specific overexpression of HtrA2/Omi suggest a neuroprotective role for HtrA2/Omi. Biochemical and biophysical research communications 28 17707776
2014 HtrA2/Omi influences the stability of LON protease 1 and prohibitin, proteins involved in mitochondrial homeostasis. Experimental cell research 27 25094062
2008 Omi / HtrA2 is relevant to the selective vulnerability of striatal neurons in Huntington's disease. The European journal of neuroscience 27 18662332
2017 Staurosporine suppresses survival of HepG2 cancer cells through Omi/HtrA2-mediated inhibition of PI3K/Akt signaling pathway. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 26 28349827
2010 Altered enzymatic activity and allele frequency of OMI/HTRA2 in Alzheimer's disease. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 21163861
2008 HtrA2 enhances the apoptotic functions of p73 on bax. Cell death and differentiation 26 18259191
2003 Immunohistochemical analysis of Omi/HtrA2 expression in stomach cancer. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 26 12887511
2022 The Improvement of Sepsis-Associated Encephalopathy by P2X7R Inhibitor through Inhibiting the Omi/HtrA2 Apoptotic Signaling Pathway. Behavioural neurology 25 35126784
2020 Acetaldehyde dehydrogenase 2 deficiency increases mitochondrial reactive oxygen species emission and induces mitochondrial protease Omi/HtrA2 in skeletal muscle. American journal of physiology. Regulatory, integrative and comparative physiology 25 32048867
2010 Omi/HtrA2 protease is associated with tubular cell apoptosis and fibrosis induced by unilateral ureteral obstruction. American journal of physiology. Renal physiology 25 20219823
2018 The mitochondrial protease HtrA2 restricts the NLRP3 and AIM2 inflammasomes. Scientific reports 24 29855523
2009 The serine protease HtrA2/Omi cleaves Parkin and irreversibly inactivates its E3 ubiquitin ligase activity. Biochemical and biophysical research communications 24 19631192
2019 Serine Protease HtrA2/Omi Deficiency Impairs Mitochondrial Homeostasis and Promotes Hepatic Fibrogenesis via Activation of Hepatic Stellate Cells. Cells 22 31547195
2009 UCF-101, a novel Omi/HtrA2 inhibitor, protects against cerebral ischemia/reperfusion injury in rats. Anatomical record (Hoboken, N.J. : 2007) 22 19462455
2008 The interaction of DIAP1 with dOmi/HtrA2 regulates cell death in Drosophila. Cell death and differentiation 22 18259196
2004 Expression of the Staphylococcus aureus surface proteins HtrA1 and HtrA2 in Lactococcus lactis. FEMS microbiology letters 22 15321674
2018 Increased Active OMI/HTRA2 Serine Protease Displays a Positive Correlation with Cholinergic Alterations in the Alzheimer's Disease Brain. Molecular neurobiology 21 30361890
2012 The protease Omi cleaves the mitogen-activated protein kinase kinase MEK1 to inhibit microglial activation. Science signaling 21 22912494
2010 The mitochondrial serine protease HtrA2/Omi cleaves RIP1 during apoptosis of Ba/F3 cells induced by growth factor withdrawal. Cell research 21 20125124

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