HtrA2 (Omi) is the Drosophila orthologue of the mitochondrial HtrA-family serine protease HTRA2/Omi, comprising a trypsin-like serine protease domain and a C-terminal PDZ domain. It is imported into mitochondria, where it resides in the intermembrane space and undergoes processive proteolytic maturation that exposes N-terminal IAP-binding motifs. Upon apoptotic stimuli mature HtrA2 is released from the intermembrane space, binds the BIR domains of DIAP1 and proteolytically cleaves and degrades DIAP1, relieving caspase inhibition and promoting cell death when overexpressed; DIAP1 in turn ubiquitinates HtrA2. Loss-of-function studies indicate it is largely dispensable for developmental and stress-induced apoptosis but required, through its catalytic activity, for the spontaneous death of male germ cells in the testis. It acts genetically downstream of Pink1 in some assays, and is processed by the mitochondrial rhomboid protease Rhomboid-7.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004252 serine-type endopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: HtrA2 is a serine endopeptidase. Reason: Conserved HtrA protease; fly HtrA2 cleaves DIAP1 directly and germ cell death depends on its catalytic activity. Supporting Evidence: PMID:17397804 DmHtrA2 specifically cleaves Drosophila inhibitor-of-apoptosis protein 1 (DIAP1) PMID:17557079 dOmi alleviates DIAP1 inhibition of all caspases by proteolytically degrading DIAP1 |
| GO:0004252 serine-type endopeptidase activity | IDA PMID:17557079 Drosophila Omi, a mitochondrial-localized IAP antagonist and... | ACCEPT | Summary: HtrA2 is a serine endopeptidase. Reason: Conserved HtrA protease; fly HtrA2 cleaves DIAP1 directly and germ cell death depends on its catalytic activity. Supporting Evidence: PMID:17397804 DmHtrA2 specifically cleaves Drosophila inhibitor-of-apoptosis protein 1 (DIAP1) PMID:17557079 dOmi alleviates DIAP1 inhibition of all caspases by proteolytically degrading DIAP1 |
| GO:0004252 serine-type endopeptidase activity | IEA GO_REF:0000002 | ACCEPT | Summary: HtrA2 is a serine endopeptidase. Reason: Conserved HtrA protease; fly HtrA2 cleaves DIAP1 directly and germ cell death depends on its catalytic activity. Supporting Evidence: PMID:17397804 DmHtrA2 specifically cleaves Drosophila inhibitor-of-apoptosis protein 1 (DIAP1) PMID:17557079 dOmi alleviates DIAP1 inhibition of all caspases by proteolytically degrading DIAP1 |
| GO:0004252 serine-type endopeptidase activity | IMP PMID:17397804 Evolution of mitochondrial cell death pathway: Proapoptotic ... | ACCEPT | Summary: HtrA2 is a serine endopeptidase. Reason: Conserved HtrA protease; fly HtrA2 cleaves DIAP1 directly and germ cell death depends on its catalytic activity. Supporting Evidence: PMID:17397804 DmHtrA2 specifically cleaves Drosophila inhibitor-of-apoptosis protein 1 (DIAP1) PMID:17557079 dOmi alleviates DIAP1 inhibition of all caspases by proteolytically degrading DIAP1 |
| GO:0004252 serine-type endopeptidase activity | IMP PMID:17557079 Drosophila Omi, a mitochondrial-localized IAP antagonist and... | ACCEPT | Summary: HtrA2 is a serine endopeptidase. Reason: Conserved HtrA protease; fly HtrA2 cleaves DIAP1 directly and germ cell death depends on its catalytic activity. Supporting Evidence: PMID:17397804 DmHtrA2 specifically cleaves Drosophila inhibitor-of-apoptosis protein 1 (DIAP1) PMID:17557079 dOmi alleviates DIAP1 inhibition of all caspases by proteolytically degrading DIAP1 |
| GO:0004252 serine-type endopeptidase activity | IMP PMID:18259196 The interaction of DIAP1 with dOmi/HtrA2 regulates cell deat... | ACCEPT | Summary: HtrA2 is a serine endopeptidase. Reason: Conserved HtrA protease; fly HtrA2 cleaves DIAP1 directly and germ cell death depends on its catalytic activity. Supporting Evidence: PMID:17397804 DmHtrA2 specifically cleaves Drosophila inhibitor-of-apoptosis protein 1 (DIAP1) PMID:17557079 dOmi alleviates DIAP1 inhibition of all caspases by proteolytically degrading DIAP1 |
| GO:0005515 protein binding | IPI PMID:17397804 Evolution of mitochondrial cell death pathway: Proapoptotic ... | MODIFY | Summary: Mature HtrA2 binds DIAP1 BIR domains via its IAP-binding motifs. Reason: The interaction is specific and mechanistically central to IAP antagonism. Mature HtrA2 binds the BIR1/BIR2 domains of DIAP1, so BIR domain binding is the informative replacement for bare protein binding; the protease activity on DIAP1 is captured by serine-type endopeptidase activity. Proposed replacements: BIR domain binding Supporting Evidence: PMID:18259196 DIAP1 was able to bind to both isoforms via its BIR1 and BIR2 domains PMID:17557079 binds selectively to the baculovirus IAP repeat 2 (BIR2) domain in Drosophila IAP1 (DIAP1) |
| GO:0005515 protein binding | IPI PMID:18259196 The interaction of DIAP1 with dOmi/HtrA2 regulates cell deat... | MODIFY | Summary: Mature HtrA2 binds DIAP1 BIR domains via its IAP-binding motifs. Reason: The interaction is specific and mechanistically central to IAP antagonism. Mature HtrA2 binds the BIR1/BIR2 domains of DIAP1, so BIR domain binding is the informative replacement for bare protein binding; the protease activity on DIAP1 is captured by serine-type endopeptidase activity. Proposed replacements: BIR domain binding Supporting Evidence: PMID:18259196 DIAP1 was able to bind to both isoforms via its BIR1 and BIR2 domains PMID:17557079 binds selectively to the baculovirus IAP repeat 2 (BIR2) domain in Drosophila IAP1 (DIAP1) |
| GO:0005515 protein binding | IPI PMID:19048081 Rhomboid-7 and HtrA2/Omi act in a common pathway with the Pa... | REMOVE | Summary: Interaction from the Rhomboid-7/Pink1 pathway study. Reason: Bare protein binding is uninformative; the relevant biology (Rhomboid-7 cleavage of the HtrA2 precursor) is an activity of Rhomboid-7, not of HtrA2. Removal does not imply the interaction is false. Supporting Evidence: PMID:19048081 showed that it is required to cleave the precursor forms of both Pink1 and Omi |
| GO:0005739 mitochondrion | IDA PMID:18259196 The interaction of DIAP1 with dOmi/HtrA2 regulates cell deat... | ACCEPT | Summary: HtrA2 is a mitochondrial protein. Reason: Directly observed mitochondrial import and residence. Supporting Evidence: PMID:18259196 Drosophila Omi/HtrA2 is imported into the mitochondria where it undergoes proteolytic maturation |
| GO:0005739 mitochondrion | IDA PMID:19048081 Rhomboid-7 and HtrA2/Omi act in a common pathway with the Pa... | ACCEPT | Summary: HtrA2 is a mitochondrial protein. Reason: Directly observed mitochondrial import and residence. Supporting Evidence: PMID:18259196 Drosophila Omi/HtrA2 is imported into the mitochondria where it undergoes proteolytic maturation |
| GO:0005739 mitochondrion | IEA GO_REF:0000117 | ACCEPT | Summary: HtrA2 is a mitochondrial protein. Reason: Directly observed mitochondrial import and residence. Supporting Evidence: PMID:18259196 Drosophila Omi/HtrA2 is imported into the mitochondria where it undergoes proteolytic maturation |
| GO:0005758 mitochondrial intermembrane space | IDA PMID:17397804 Evolution of mitochondrial cell death pathway: Proapoptotic ... | ACCEPT | Summary: HtrA2 resides in the mitochondrial intermembrane space. Reason: Fractionation shows IMS localization, conserved with mammalian HTRA2. Supporting Evidence: PMID:17557079 a developmentally regulated mitochondrial intermembrane space protein |
| GO:0005758 mitochondrial intermembrane space | IDA PMID:17557079 Drosophila Omi, a mitochondrial-localized IAP antagonist and... | ACCEPT | Summary: HtrA2 resides in the mitochondrial intermembrane space. Reason: Fractionation shows IMS localization, conserved with mammalian HTRA2. Supporting Evidence: PMID:17557079 a developmentally regulated mitochondrial intermembrane space protein |
| GO:0005758 mitochondrial intermembrane space | IDA PMID:18259196 The interaction of DIAP1 with dOmi/HtrA2 regulates cell deat... | ACCEPT | Summary: HtrA2 resides in the mitochondrial intermembrane space. Reason: Fractionation shows IMS localization, conserved with mammalian HTRA2. Supporting Evidence: PMID:17557079 a developmentally regulated mitochondrial intermembrane space protein |
| GO:0005758 mitochondrial intermembrane space | IEA GO_REF:0000044 | ACCEPT | Summary: HtrA2 resides in the mitochondrial intermembrane space. Reason: Fractionation shows IMS localization, conserved with mammalian HTRA2. Supporting Evidence: PMID:17557079 a developmentally regulated mitochondrial intermembrane space protein |
| GO:0005829 cytosol | IDA PMID:17557079 Drosophila Omi, a mitochondrial-localized IAP antagonist and... | KEEP AS NON CORE | Summary: Mature HtrA2 is released to the cytosol upon apoptotic stimuli. Reason: Stimulus-dependent location; one study reports it remains near mitochondria rather than diffusing. Supporting Evidence: PMID:17557079 mature dOmi is then differentially released into the cytosol |
| GO:0006508 proteolysis | IBA GO_REF:0000033 | ACCEPT | Summary: HtrA2 mediates proteolysis. Reason: General but correct for a serine protease. Supporting Evidence: PMID:17557079 dOmi alleviates DIAP1 inhibition of all caspases by proteolytically degrading DIAP1 |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | ACCEPT | Summary: HtrA2 mediates proteolysis. Reason: General but correct for a serine protease. Supporting Evidence: PMID:17557079 dOmi alleviates DIAP1 inhibition of all caspases by proteolytically degrading DIAP1 |
| GO:0007005 mitochondrion organization | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: HtrA2 contributes to mitochondrial integrity. Reason: Some mutant phenotypes resemble pink1/parkin, but an independent null analysis found no mitochondrial morphology defects; the role is modest and contested. Supporting Evidence: PMID:19282869 suggesting that it may function in maintaining mitochondrial integrity PMID:19118185 do not show mitochondrial morphological defects |
| GO:0007005 mitochondrion organization | IMP PMID:19282869 Drosophila HtrA2 is dispensable for apoptosis but acts downs... | KEEP AS NON CORE | Summary: HtrA2 contributes to mitochondrial integrity. Reason: Some mutant phenotypes resemble pink1/parkin, but an independent null analysis found no mitochondrial morphology defects; the role is modest and contested. Supporting Evidence: PMID:19282869 suggesting that it may function in maintaining mitochondrial integrity PMID:19118185 do not show mitochondrial morphological defects |
| GO:0007283 spermatogenesis | IMP PMID:19118185 Loss-of-function analysis suggests that Omi/HtrA2 is not an ... | KEEP AS NON CORE | Summary: HtrA2 null males show spermatogenesis defects. Reason: Tissue-specific mutant phenotype; the more specific known role is in testis germ cell death. |
| GO:0008233 peptidase activity | IDA PMID:18259196 The interaction of DIAP1 with dOmi/HtrA2 regulates cell deat... | MODIFY | Summary: HtrA2 has peptidase activity. Reason: Correct but an uninformative parent; MODIFY to serine-type endopeptidase activity, which HtrA2 already carries (IBA, IDA, IEA, IMP). Proposed replacements: serine-type endopeptidase activity Supporting Evidence: PMID:18259196 further degradation of the BIR1 domain by the proteolytic activity of dOmi |
| GO:0008233 peptidase activity | IDA PMID:19282869 Drosophila HtrA2 is dispensable for apoptosis but acts downs... | MODIFY | Summary: HtrA2 has peptidase activity. Reason: Correct but an uninformative parent; MODIFY to serine-type endopeptidase activity, which HtrA2 already carries (IBA, IDA, IEA, IMP). Proposed replacements: serine-type endopeptidase activity Supporting Evidence: PMID:18259196 further degradation of the BIR1 domain by the proteolytic activity of dOmi |
| GO:0008233 peptidase activity | IEA GO_REF:0000117 | MODIFY | Summary: HtrA2 has peptidase activity. Reason: Correct but an uninformative parent; MODIFY to serine-type endopeptidase activity, which HtrA2 already carries (IBA, IDA, IEA, IMP). Proposed replacements: serine-type endopeptidase activity Supporting Evidence: PMID:18259196 further degradation of the BIR1 domain by the proteolytic activity of dOmi |
| GO:0012501 programmed cell death | IBA GO_REF:0000033 | ACCEPT | Summary: HtrA2 promotes programmed cell death. Reason: Overexpression induces death, and HtrA2 is required for spontaneous male germ cell death. Supporting Evidence: PMID:23523076 as an important mediator of GCD, acting mainly through its catalytic activity |
| GO:0012501 programmed cell death | IEA GO_REF:0000117 | ACCEPT | Summary: HtrA2 promotes programmed cell death. Reason: Overexpression induces death, and HtrA2 is required for spontaneous male germ cell death. Supporting Evidence: PMID:23523076 as an important mediator of GCD, acting mainly through its catalytic activity |
| GO:0016006 Nebenkern | IDA PMID:19118185 Loss-of-function analysis suggests that Omi/HtrA2 is not an ... | ACCEPT | Summary: HtrA2 localizes to the Nebenkern, the fused mitochondrial derivative of spermatids. Reason: Consistent with mitochondrial localization in male germ cells. |
| GO:0016020 membrane | IEA GO_REF:0000117 | MODIFY | Summary: Generic membrane annotation. Reason: The precursor is membrane-anchored in the mitochondrial inner membrane; correct but uninformative, so MODIFY to mitochondrial membrane, which HtrA2 already carries (EXP, IEA). Proposed replacements: mitochondrial membrane |
| GO:0017171 serine hydrolase activity | HDA PMID:33827210 A Superfamily-wide Activity Atlas of Serine Hydrolases in &l... | MODIFY | Summary: Active serine hydrolase detected by activity-based profiling. Reason: HDA chemoproteomics detection of an active serine hydrolase; correct but an uninformative parent, so MODIFY to serine-type endopeptidase activity, which HtrA2 already carries (IBA, IDA, IEA, IMP). The HtrA2-specific row is in the supplementary data, not in the cached text, so no supporting quote is given. Proposed replacements: serine-type endopeptidase activity |
| GO:0031966 mitochondrial membrane | EXP PMID:18259196 The interaction of DIAP1 with dOmi/HtrA2 regulates cell deat... | ACCEPT | Summary: HtrA2 precursor associates with the mitochondrial (inner) membrane. Reason: Consistent with inner membrane anchoring prior to maturation and release. Supporting Evidence: PMID:18259196 Drosophila Omi/HtrA2 is imported into the mitochondria where it undergoes proteolytic maturation |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000044 | ACCEPT | Summary: HtrA2 precursor associates with the mitochondrial (inner) membrane. Reason: Consistent with inner membrane anchoring prior to maturation and release. Supporting Evidence: PMID:18259196 Drosophila Omi/HtrA2 is imported into the mitochondria where it undergoes proteolytic maturation |
| GO:0035234 ectopic germ cell programmed cell death | IMP PMID:23523076 Alternative germ cell death pathway in Drosophila involves H... | MODIFY | Summary: HtrA2 is required for spontaneous male germ cell death in the testis. Reason: The cited study concerns germ cells eliminated within the testis before meiosis, not errant germ cells outside the gonad or migratory path as required by the definition of ectopic germ cell programmed cell death; the general programmed cell death term fits. GO has no germ-cell-specific programmed cell death term other than the ectopic one; the intermediate ancestor programmed cell death involved in cell development was considered but does not describe pre-meiotic elimination of spermatogonia better. Because programmed cell death is already present (IBA, IEA), this MODIFY amounts in practice to dropping the mis-fitting specific term. The same row on Dronc is treated identically. Proposed replacements: programmed cell death Supporting Evidence: PMID:23523076 almost one-third of the newly emerging male germ cells are spontaneously eliminated before entering meiosis |
| GO:0042981 regulation of apoptotic process | IMP PMID:17397804 Evolution of mitochondrial cell death pathway: Proapoptotic ... | MODIFY | Summary: HtrA2 regulates apoptosis through DIAP1. Reason: Correct but sign-neutral; HtrA2 promotes apoptosis by binding and degrading DIAP1, so MODIFY to positive regulation of apoptotic process, which HtrA2 already carries (IBA, IDA, IEA, IMP). Proposed replacements: positive regulation of apoptotic process Supporting Evidence: PMID:17397804 DmHtrA2 promotes cell death through a cleavage of DIAP1 in the vicinity of mitochondria |
| GO:0042981 regulation of apoptotic process | IMP PMID:17557079 Drosophila Omi, a mitochondrial-localized IAP antagonist and... | MODIFY | Summary: HtrA2 regulates apoptosis through DIAP1. Reason: Correct but sign-neutral; HtrA2 promotes apoptosis by binding and degrading DIAP1, so MODIFY to positive regulation of apoptotic process, which HtrA2 already carries (IBA, IDA, IEA, IMP). Proposed replacements: positive regulation of apoptotic process Supporting Evidence: PMID:17397804 DmHtrA2 promotes cell death through a cleavage of DIAP1 in the vicinity of mitochondria |
| GO:0042981 regulation of apoptotic process | IMP PMID:18259196 The interaction of DIAP1 with dOmi/HtrA2 regulates cell deat... | MODIFY | Summary: HtrA2 regulates apoptosis through DIAP1. Reason: Correct but sign-neutral; HtrA2 promotes apoptosis by binding and degrading DIAP1, so MODIFY to positive regulation of apoptotic process, which HtrA2 already carries (IBA, IDA, IEA, IMP). Proposed replacements: positive regulation of apoptotic process Supporting Evidence: PMID:17397804 DmHtrA2 promotes cell death through a cleavage of DIAP1 in the vicinity of mitochondria |
| GO:0043065 positive regulation of apoptotic process | IBA GO_REF:0000033 | ACCEPT | Summary: HtrA2 promotes apoptosis as an IAP antagonist. Reason: Gain-of-function and biochemical data show HtrA2 degrades DIAP1 and induces caspase-dependent death; note that loss of HtrA2 does not block developmental or stress-induced apoptosis. Supporting Evidence: PMID:17557079 induces apoptosis both in cultured cells and in the developing fly eye PMID:19282869 we find HtrA2 appears to be dispensable for developmental or stress-induced apoptosis |
| GO:0043065 positive regulation of apoptotic process | IDA PMID:17557079 Drosophila Omi, a mitochondrial-localized IAP antagonist and... | ACCEPT | Summary: HtrA2 promotes apoptosis as an IAP antagonist. Reason: Gain-of-function and biochemical data show HtrA2 degrades DIAP1 and induces caspase-dependent death; note that loss of HtrA2 does not block developmental or stress-induced apoptosis. Supporting Evidence: PMID:17557079 induces apoptosis both in cultured cells and in the developing fly eye PMID:19282869 we find HtrA2 appears to be dispensable for developmental or stress-induced apoptosis |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000117 | ACCEPT | Summary: HtrA2 promotes apoptosis as an IAP antagonist. Reason: Gain-of-function and biochemical data show HtrA2 degrades DIAP1 and induces caspase-dependent death; note that loss of HtrA2 does not block developmental or stress-induced apoptosis. Supporting Evidence: PMID:17557079 induces apoptosis both in cultured cells and in the developing fly eye PMID:19282869 we find HtrA2 appears to be dispensable for developmental or stress-induced apoptosis |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:17557079 Drosophila Omi, a mitochondrial-localized IAP antagonist and... | ACCEPT | Summary: HtrA2 promotes apoptosis as an IAP antagonist. Reason: Gain-of-function and biochemical data show HtrA2 degrades DIAP1 and induces caspase-dependent death; note that loss of HtrA2 does not block developmental or stress-induced apoptosis. Supporting Evidence: PMID:17557079 induces apoptosis both in cultured cells and in the developing fly eye PMID:19282869 we find HtrA2 appears to be dispensable for developmental or stress-induced apoptosis |
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Download this section (compressed HTML)Q: BIR domain binding captures the DIAP1 interaction of HtrA2 and Prx4/Jafrac2; should GO also provide a molecular function term for IAP antagonism by IBM-mediated competitive displacement of caspases, shared with the RHG proteins?
Q: Which substrates does HtrA2 cleave during male germ cell death, given that this role relies on catalysis rather than IAP antagonism?
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