RIPK3 (receptor-interacting serine/threonine-protein kinase 3) is a cytosolic protein kinase with an N-terminal kinase domain and a C-terminal RIP homotypic interaction motif (RHIM). It is the essential kinase of necroptosis, a caspase-independent, lytic and inflammatory form of programmed cell death. Upon death-receptor (TNFR1), TLR3/4-TRIF or ZBP1 signaling under conditions of low caspase-8 activity, RIPK3 is recruited through RHIM-RHIM interactions with RIPK1, TRIF or ZBP1 into the necrosome, a hetero-amyloid fibrillar signaling complex; RIPK3 RHIM polymerization drives RIPK3 autophosphorylation and activation. Activated RIPK3 phosphorylates the pseudokinase MLKL (T357/S358 in human), triggering MLKL oligomerization, plasma-membrane translocation and membrane rupture. RIPK3 also takes part in reciprocal phosphorylation with RIPK1. It shuttles between nucleus and cytoplasm, is restrained by caspase-8 cleavage and by E3 ligases such as PELI1 that degrade kinase-active RIPK3, and is targeted by herpesvirus RHIM proteins, consistent with a role of necroptosis in antiviral defense and inflammatory tissue injury.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001914 regulation of T cell mediated cytotoxicity | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'regulation of T cell mediated cytotoxicity'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0001914 regulation of T cell mediated cytotoxicity | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'regulation of T cell mediated cytotoxicity'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0002819 regulation of adaptive immune response | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'regulation of adaptive immune response'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0002819 regulation of adaptive immune response | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'regulation of adaptive immune response'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0003713 transcription coactivator activity | TAS PMID:10339433 Identification of RIP3, a RIP-like kinase that activates apo... | REMOVE | Summary: TAS annotation of transcription coactivator activity based on the original RIP3 cloning paper. Reason: PMID:10339433 reports that the overexpressed RIP3 C-terminus activates NF-kappaB reporter activity; it does not show that RIPK3 binds transcription factors or the transcriptional machinery to coactivate transcription. NF-kappaB activation by RIPK3 is weak and indirect, and other work reports attenuation. No evidence supports coactivator activity. Supporting Evidence: PMID:10339433 The carboxy-terminal domain of RIP3, like that of RIP, could activate the transcription factor NFkappaB and induce apoptosis when expressed in mammalian cells. PMID:10358032 RIP3, however, attenuates both RIP and TNF receptor-1-induced NF-kappaB activation. PMID:21931591 Because RIP3 is a weak inducer of NF-ΞΊB |
| GO:0004672 protein kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation of protein kinase activity. Reason: Correct; RIPK3 is an active protein kinase (substrates MLKL and RIPK1). The more specific GO:0004674 is also annotated. Supporting Evidence: PMID:22265413 MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. |
| GO:0004672 protein kinase activity | IDA PMID:22265413 Mixed lineage kinase domain-like protein mediates necrosis s... | ACCEPT | Summary: IDA: RIPK3 phosphorylates MLKL on T357/S358 (PMID:22265413). Reason: Correct; RIPK3 is an active protein kinase. The more specific protein serine/threonine kinase activity (GO:0004674) is also annotated and is the preferred core term. Supporting Evidence: PMID:22265413 MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation of protein kinase activity. Reason: Correct; RIPK3 is an active protein kinase (substrates MLKL and RIPK1). The more specific GO:0004674 is also annotated. |
| GO:0004672 protein kinase activity | IMP PMID:22817896 The RIP1/RIP3 necrosome forms a functional amyloid signaling... | ACCEPT | Summary: IMP: RHIM mutations that block RIP1/RIP3 assembly compromise kinase activation. Reason: Kinase activity is the core RIPK3 function; the evidence shows that RHIM-dependent assembly is required for that activity. GO:0004674 is the more specific term already annotated. Supporting Evidence: PMID:22817896 Mutations in the RHIMs of RIP1 and RIP3 that are defective in the interaction compromise cluster formation, kinase activation, and programmed necrosis in vivo. |
| GO:0004672 protein kinase activity | IMP PMID:29883609 PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylat... | ACCEPT | Summary: IMP: T182 phosphorylation is required for RIP3 kinase activity (PMID:29883609). Reason: Supports intrinsic kinase activity of RIPK3; consistent with its core necroptotic kinase role. Supporting Evidence: PMID:29883609 This same phosphorylation event is also important for RIP3 kinase activity; thus, PELI1 preferentially targets kinase-active RIP3 for degradation. |
| GO:0004672 protein kinase activity | TAS PMID:10358032 RIP3, a novel apoptosis-inducing kinase. | ACCEPT | Summary: TAS from the RIP3 cloning paper, based on the N-terminal kinase domain. Reason: RIPK3 has a canonical N-terminal kinase domain with demonstrated catalytic activity (see GO:0004674 annotations). Supporting Evidence: PMID:10358032 RIP3 is a novel gene product containing a N-terminal kinase domain that shares extensive homology with the corresponding domain in RIP (receptor-interacting protein) and RIP2. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:19524513 Phosphorylation-driven assembly of the RIP1-RIP3 complex reg... | ACCEPT | Summary: IDA annotation of protein serine/threonine kinase activity (PMID:19524513). Reason: Core function. RIPK3 phosphorylates MLKL on T357 and S358, the key necroptotic execution step, and participates in reciprocal phosphorylation with RIPK1; its kinase activity is essential for necroptosis. Supporting Evidence: PMID:19524513 RIP3 regulates necrosis-specific RIP1 phosphorylation. PMID:19524513 The phosphorylation of RIP1 and RIP3 stabilizes their association within the pronecrotic complex, activates the pronecrotic kinase activity, and triggers downstream reactive oxygen species production. |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation of protein serine/threonine kinase activity (GO_REF:0000120). Reason: Core function. RIPK3 phosphorylates MLKL on T357 and S358, the key necroptotic execution step, and participates in reciprocal phosphorylation with RIPK1; its kinase activity is essential for necroptosis. Supporting Evidence: PMID:19524512 The kinase activity of RIP3 is essential for necrosis execution. |
| GO:0004674 protein serine/threonine kinase activity | IMP PMID:22265414 The mitochondrial phosphatase PGAM5 functions at the converg... | ACCEPT | Summary: IMP annotation of protein serine/threonine kinase activity (PMID:22265414). Reason: Core function. RIPK3 phosphorylates MLKL on T357 and S358, the key necroptotic execution step, and participates in reciprocal phosphorylation with RIPK1; its kinase activity is essential for necroptosis. Supporting Evidence: PMID:22265414 The programmed necrosis induced by TNF-Ξ± requires the activities of the receptor-interacting serine-threonine kinases RIP1 and RIP3 and their interaction with the mixed lineage kinase domain-like protein MLKL. |
| GO:0004674 protein serine/threonine kinase activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation of protein serine/threonine kinase activity (GO_REF:0000024). Reason: Core function. RIPK3 phosphorylates MLKL on T357 and S358, the key necroptotic execution step, and participates in reciprocal phosphorylation with RIPK1; its kinase activity is essential for necroptosis. Supporting Evidence: PMID:22265413 MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. |
| GO:0004674 protein serine/threonine kinase activity | TAS PMID:10339433 Identification of RIP3, a RIP-like kinase that activates apo... | ACCEPT | Summary: TAS annotation of protein serine/threonine kinase activity (PMID:10339433). Reason: Core function. RIPK3 phosphorylates MLKL on T357 and S358, the key necroptotic execution step, and participates in reciprocal phosphorylation with RIPK1; its kinase activity is essential for necroptosis. Supporting Evidence: PMID:19524512 The kinase activity of RIP3 is essential for necrosis execution. |
| GO:0004674 protein serine/threonine kinase activity | TAS Reactome:R-HSA-5218906 | ACCEPT | Summary: TAS annotation of protein serine/threonine kinase activity (Reactome:R-HSA-5218906). Reason: Core function. RIPK3 phosphorylates MLKL on T357 and S358, the key necroptotic execution step, and participates in reciprocal phosphorylation with RIPK1; its kinase activity is essential for necroptosis. Supporting Evidence: Reactome:R-HSA-5218906 Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) was shown to activate mixed lineage kinase domain-like protein (MLKL) by phosphorylation of the threonine 357 (T357) and serine 358 (S358) residues |
| GO:0005515 protein binding | IPI PMID:19524512 Receptor interacting protein kinase-3 determines cellular ne... | MODIFY | Summary: IPI evidence (PMID:19524512) for binding of RIPK3 to RIPK1, its RHIM partner and co-kinase in the necrosome. Reason: GO:0005515 protein binding is uninformative. The RIPK1-RIPK3 interaction is a specific RHIM-mediated hetero-assembly between two serine/threonine kinases, so the informative MF is protein serine/threonine kinase binding (GO:0120283), which is also annotated to RIPK3 by EXP/IPI evidence. Proposed replacements: protein serine/threonine kinase binding Supporting Evidence: PMID:19524512 Upon induction of necrosis, RIP3 is recruited to RIPK1 to form a necrosis-inducing complex. |
| GO:0005515 protein binding | IPI PMID:19524513 Phosphorylation-driven assembly of the RIP1-RIP3 complex reg... | MODIFY | Summary: IPI evidence (PMID:19524513) for binding of RIPK3 to RIPK1, its RHIM partner and co-kinase in the necrosome. Reason: GO:0005515 protein binding is uninformative. The RIPK1-RIPK3 interaction is a specific RHIM-mediated hetero-assembly between two serine/threonine kinases, so the informative MF is protein serine/threonine kinase binding (GO:0120283), which is also annotated to RIPK3 by EXP/IPI evidence. Proposed replacements: protein serine/threonine kinase binding Supporting Evidence: PMID:19524513 The phosphorylation of RIP1 and RIP3 stabilizes their association within the pronecrotic complex, activates the pronecrotic kinase activity, and triggers downstream reactive oxygen species production. |
| GO:0005515 protein binding | IPI PMID:19590578 DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic intera... | REMOVE | Summary: IPI evidence (PMID:19590578) for binding of RIPK3 to ZBP1/DAI. Reason: GO:0005515 protein binding conveys no functional information. The biologically meaningful content of this interaction is either captured by more specific annotations (kinase activity toward MLKL; RHIM-mediated necrosome assembly; serine/threonine kinase binding for RIPK1) or reflects regulation of RIPK3 by another protein (E3 ligases, viral RHIM inhibitors, pharmacological perturbation) rather than a RIPK3 molecular function. Supporting Evidence: PMID:19590578 these domains relay DAI-induced NF-kappaB signals through the recruitment of the RHIM-containing kinases RIP1 and RIP3 |
| GO:0005515 protein binding | IPI PMID:21887730 Control of NOD2 and Rip2-dependent innate immune activation ... | REMOVE | Summary: IPI evidence (PMID:21887730) for binding of RIPK3 to ARHGEF2/GEF-H1. Reason: GO:0005515 protein binding conveys no functional information. The biologically meaningful content of this interaction is either captured by more specific annotations (kinase activity toward MLKL; RHIM-mediated necrosome assembly; serine/threonine kinase binding for RIPK1) or reflects regulation of RIPK3 by another protein (E3 ligases, viral RHIM inhibitors, pharmacological perturbation) rather than a RIPK3 molecular function. Supporting Evidence: PMID:21887730 Immunocomplexes forming in the presence of GEF-H1 contained Rip1, Rip2 and Rip3 |
| GO:0005515 protein binding | IPI PMID:21931591 cIAP1/2 are direct E3 ligases conjugating diverse types of u... | REMOVE | Summary: IPI evidence (PMID:21931591) for binding of RIPK3 to BIRC3/cIAP2. Reason: GO:0005515 protein binding conveys no functional information. The biologically meaningful content of this interaction is either captured by more specific annotations (kinase activity toward MLKL; RHIM-mediated necrosome assembly; serine/threonine kinase binding for RIPK1) or reflects regulation of RIPK3 by another protein (E3 ligases, viral RHIM inhibitors, pharmacological perturbation) rather than a RIPK3 molecular function. Supporting Evidence: PMID:21931591 cIAP1 and cIAP2 are direct E3 ubiquitin ligases for all four RIP proteins |
| GO:0005515 protein binding | IPI PMID:21931591 cIAP1/2 are direct E3 ligases conjugating diverse types of u... | REMOVE | Summary: IPI evidence (PMID:21931591) for binding of RIPK3 to BIRC2/cIAP1. Reason: GO:0005515 protein binding conveys no functional information. The biologically meaningful content of this interaction is either captured by more specific annotations (kinase activity toward MLKL; RHIM-mediated necrosome assembly; serine/threonine kinase binding for RIPK1) or reflects regulation of RIPK3 by another protein (E3 ligases, viral RHIM inhibitors, pharmacological perturbation) rather than a RIPK3 molecular function. Supporting Evidence: PMID:21931591 cIAP1 and cIAP2 are direct E3 ubiquitin ligases for all four RIP proteins |
| GO:0005515 protein binding | IPI PMID:22265413 Mixed lineage kinase domain-like protein mediates necrosis s... | MODIFY | Summary: IPI evidence (PMID:22265413) for binding of RIPK3 to RIPK1, its RHIM partner and co-kinase in the necrosome. Reason: GO:0005515 protein binding is uninformative. The RIPK1-RIPK3 interaction is a specific RHIM-mediated hetero-assembly between two serine/threonine kinases, so the informative MF is protein serine/threonine kinase binding (GO:0120283), which is also annotated to RIPK3 by EXP/IPI evidence. Proposed replacements: protein serine/threonine kinase binding Supporting Evidence: PMID:22265413 MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. |
| GO:0005515 protein binding | IPI PMID:22265413 Mixed lineage kinase domain-like protein mediates necrosis s... | REMOVE | Summary: IPI evidence (PMID:22265413) for binding of RIPK3 to MLKL. Reason: GO:0005515 protein binding conveys no functional information. The biologically meaningful content of this interaction is either captured by more specific annotations (kinase activity toward MLKL; RHIM-mediated necrosome assembly; serine/threonine kinase binding for RIPK1) or reflects regulation of RIPK3 by another protein (E3 ligases, viral RHIM inhibitors, pharmacological perturbation) rather than a RIPK3 molecular function. Supporting Evidence: PMID:22265413 MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. |
| GO:0005515 protein binding | IPI PMID:22265414 The mitochondrial phosphatase PGAM5 functions at the converg... | MODIFY | Summary: IPI evidence (PMID:22265414) for binding of RIPK3 to RIPK1, its RHIM partner and co-kinase in the necrosome. Reason: GO:0005515 protein binding is uninformative. The RIPK1-RIPK3 interaction is a specific RHIM-mediated hetero-assembly between two serine/threonine kinases, so the informative MF is protein serine/threonine kinase binding (GO:0120283), which is also annotated to RIPK3 by EXP/IPI evidence. Proposed replacements: protein serine/threonine kinase binding Supporting Evidence: PMID:22265414 The programmed necrosis induced by TNF-Ξ± requires the activities of the receptor-interacting serine-threonine kinases RIP1 and RIP3 and their interaction with the mixed lineage kinase domain-like protein MLKL. |
| GO:0005515 protein binding | IPI PMID:22265414 The mitochondrial phosphatase PGAM5 functions at the converg... | REMOVE | Summary: IPI evidence (PMID:22265414) for binding of RIPK3 to MLKL. Reason: GO:0005515 protein binding conveys no functional information. The biologically meaningful content of this interaction is either captured by more specific annotations (kinase activity toward MLKL; RHIM-mediated necrosome assembly; serine/threonine kinase binding for RIPK1) or reflects regulation of RIPK3 by another protein (E3 ligases, viral RHIM inhibitors, pharmacological perturbation) rather than a RIPK3 molecular function. Supporting Evidence: PMID:22265414 The programmed necrosis induced by TNF-Ξ± requires the activities of the receptor-interacting serine-threonine kinases RIP1 and RIP3 and their interaction with the mixed lineage kinase domain-like protein MLKL. |
| GO:0005515 protein binding | IPI PMID:22817896 The RIP1/RIP3 necrosome forms a functional amyloid signaling... | MODIFY | Summary: IPI evidence (PMID:22817896) for binding of RIPK3 to RIPK1, its RHIM partner and co-kinase in the necrosome. Reason: GO:0005515 protein binding is uninformative. The RIPK1-RIPK3 interaction is a specific RHIM-mediated hetero-assembly between two serine/threonine kinases, so the informative MF is protein serine/threonine kinase binding (GO:0120283), which is also annotated to RIPK3 by EXP/IPI evidence. Proposed replacements: protein serine/threonine kinase binding Supporting Evidence: PMID:22817896 Here, we report that the RIP homotypic interaction motifs (RHIMs) of RIP1 and RIP3 mediate the assembly of heterodimeric filamentous structures. |
| GO:0005515 protein binding | IPI PMID:26559832 Herpes Simplex Virus 1 (HSV-1) and HSV-2 Mediate Species-Spe... | REMOVE | Summary: IPI evidence (PMID:26559832) for binding of RIPK3 to HSV-2 ICP10 (R1). Reason: GO:0005515 protein binding conveys no functional information. The biologically meaningful content of this interaction is either captured by more specific annotations (kinase activity toward MLKL; RHIM-mediated necrosome assembly; serine/threonine kinase binding for RIPK1) or reflects regulation of RIPK3 by another protein (E3 ligases, viral RHIM inhibitors, pharmacological perturbation) rather than a RIPK3 molecular function. Supporting Evidence: PMID:26559832 The RHIM domain of R1 was essential for its association with human RIP3 and RIP1, leading to disruption of the RIP1/RIP3 complex. |
| GO:0005515 protein binding | IPI PMID:26559832 Herpes Simplex Virus 1 (HSV-1) and HSV-2 Mediate Species-Spe... | MODIFY | Summary: IPI evidence (PMID:26559832) for binding of RIPK3 to RIPK1, its RHIM partner and co-kinase in the necrosome. Reason: GO:0005515 protein binding is uninformative. The RIPK1-RIPK3 interaction is a specific RHIM-mediated hetero-assembly between two serine/threonine kinases, so the informative MF is protein serine/threonine kinase binding (GO:0120283), which is also annotated to RIPK3 by EXP/IPI evidence. Proposed replacements: protein serine/threonine kinase binding Supporting Evidence: PMID:26559832 The RHIM domain of R1 was essential for its association with human RIP3 and RIP1, leading to disruption of the RIP1/RIP3 complex. |
| GO:0005515 protein binding | IPI PMID:29883609 PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylat... | REMOVE | Summary: IPI evidence (PMID:29883609) for binding of RIPK3 to UniProtKB:O60566. Reason: GO:0005515 protein binding conveys no functional information. The biologically meaningful content of this interaction is either captured by more specific annotations (kinase activity toward MLKL; RHIM-mediated necrosome assembly; serine/threonine kinase binding for RIPK1) or reflects regulation of RIPK3 by another protein (E3 ligases, viral RHIM inhibitors, pharmacological perturbation) rather than a RIPK3 molecular function. Supporting Evidence: PMID:29883609 This same phosphorylation event is also important for RIP3 kinase activity; thus, PELI1 preferentially targets kinase-active RIP3 for degradation. |
| GO:0005515 protein binding | IPI PMID:29883609 PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylat... | REMOVE | Summary: IPI evidence (PMID:29883609) for binding of RIPK3 to UniProtKB:Q12933. Reason: GO:0005515 protein binding conveys no functional information. The biologically meaningful content of this interaction is either captured by more specific annotations (kinase activity toward MLKL; RHIM-mediated necrosome assembly; serine/threonine kinase binding for RIPK1) or reflects regulation of RIPK3 by another protein (E3 ligases, viral RHIM inhibitors, pharmacological perturbation) rather than a RIPK3 molecular function. Supporting Evidence: PMID:29883609 This same phosphorylation event is also important for RIP3 kinase activity; thus, PELI1 preferentially targets kinase-active RIP3 for degradation. |
| GO:0005515 protein binding | IPI PMID:29883609 PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylat... | MODIFY | Summary: IPI evidence (PMID:29883609) for binding of RIPK3 to RIPK1, its RHIM partner and co-kinase in the necrosome. Reason: GO:0005515 protein binding is uninformative. The RIPK1-RIPK3 interaction is a specific RHIM-mediated hetero-assembly between two serine/threonine kinases, so the informative MF is protein serine/threonine kinase binding (GO:0120283), which is also annotated to RIPK3 by EXP/IPI evidence. Proposed replacements: protein serine/threonine kinase binding Supporting Evidence: PMID:29883609 This same phosphorylation event is also important for RIP3 kinase activity; thus, PELI1 preferentially targets kinase-active RIP3 for degradation. |
| GO:0005515 protein binding | IPI PMID:29883609 PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylat... | REMOVE | Summary: IPI evidence (PMID:29883609) for binding of RIPK3 to MLKL. Reason: GO:0005515 protein binding conveys no functional information. The biologically meaningful content of this interaction is either captured by more specific annotations (kinase activity toward MLKL; RHIM-mediated necrosome assembly; serine/threonine kinase binding for RIPK1) or reflects regulation of RIPK3 by another protein (E3 ligases, viral RHIM inhibitors, pharmacological perturbation) rather than a RIPK3 molecular function. Supporting Evidence: PMID:29883609 This same phosphorylation event is also important for RIP3 kinase activity; thus, PELI1 preferentially targets kinase-active RIP3 for degradation. |
| GO:0005515 protein binding | IPI PMID:29883609 PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylat... | REMOVE | Summary: IPI evidence (PMID:29883609) for binding of RIPK3 to UniProtKB:Q96FA3. Reason: GO:0005515 protein binding conveys no functional information. The biologically meaningful content of this interaction is either captured by more specific annotations (kinase activity toward MLKL; RHIM-mediated necrosome assembly; serine/threonine kinase binding for RIPK1) or reflects regulation of RIPK3 by another protein (E3 ligases, viral RHIM inhibitors, pharmacological perturbation) rather than a RIPK3 molecular function. Supporting Evidence: PMID:29883609 This same phosphorylation event is also important for RIP3 kinase activity; thus, PELI1 preferentially targets kinase-active RIP3 for degradation. |
| GO:0005515 protein binding | IPI PMID:29883609 PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylat... | REMOVE | Summary: IPI evidence (PMID:29883609) for binding of RIPK3 to UniProtKB:Q9UNE7. Reason: GO:0005515 protein binding conveys no functional information. The biologically meaningful content of this interaction is either captured by more specific annotations (kinase activity toward MLKL; RHIM-mediated necrosome assembly; serine/threonine kinase binding for RIPK1) or reflects regulation of RIPK3 by another protein (E3 ligases, viral RHIM inhibitors, pharmacological perturbation) rather than a RIPK3 molecular function. Supporting Evidence: PMID:29883609 This same phosphorylation event is also important for RIP3 kinase activity; thus, PELI1 preferentially targets kinase-active RIP3 for degradation. |
| GO:0005515 protein binding | IPI PMID:30185776 SARS-Coronavirus Open Reading Frame-3a drives multimodal nec... | REMOVE | Summary: IPI evidence (PMID:30185776) for binding of RIPK3 to SARS-CoV ORF3a. Reason: GO:0005515 protein binding conveys no functional information. The biologically meaningful content of this interaction is either captured by more specific annotations (kinase activity toward MLKL; RHIM-mediated necrosome assembly; serine/threonine kinase binding for RIPK1) or reflects regulation of RIPK3 by another protein (E3 ligases, viral RHIM inhibitors, pharmacological perturbation) rather than a RIPK3 molecular function. Supporting Evidence: PMID:30185776 We show that SARS 3a interacts with Receptor Interacting Protein 3 (Rip3), which augments the oligomerization of SARS 3a helping drive necrotic cell death. |
| GO:0005515 protein binding | IPI PMID:33348174 Herpes simplex virus encoded ICP6 protein forms functional a... | REMOVE | Summary: IPI evidence (PMID:33348174) for binding of RIPK3 to HSV-1 ICP6 (R1). Reason: GO:0005515 protein binding conveys no functional information. The biologically meaningful content of this interaction is either captured by more specific annotations (kinase activity toward MLKL; RHIM-mediated necrosome assembly; serine/threonine kinase binding for RIPK1) or reflects regulation of RIPK3 by another protein (E3 ligases, viral RHIM inhibitors, pharmacological perturbation) rather than a RIPK3 molecular function. Supporting Evidence: PMID:33348174 the ICP6 RHIM is amyloidogenic and can interact with host RHIM-containing proteins to form heteromeric amyloid complexes |
| GO:0005515 protein binding | IPI PMID:37089942 Curcumin alleviates experimental colitis in mice by suppress... | MODIFY | Summary: IPI evidence (PMID:37089942) for binding of RIPK3 to RIPK1, its RHIM partner and co-kinase in the necrosome. Reason: GO:0005515 protein binding is uninformative. The RIPK1-RIPK3 interaction is a specific RHIM-mediated hetero-assembly between two serine/threonine kinases, so the informative MF is protein serine/threonine kinase binding (GO:0120283), which is also annotated to RIPK3 by EXP/IPI evidence. Proposed replacements: protein serine/threonine kinase binding Supporting Evidence: PMID:37089942 Co-Immunoprecipitation assay showed that curcumin weakened the interaction between RIP1 and RIP3 |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based IEA for ATP binding via the protein kinase domain. Reason: RIPK3 is a catalytically active kinase and necessarily binds ATP; correct but implied by the kinase activity. |
| GO:0005634 nucleus | IDA PMID:30271893 Nuclear RIPK3 and MLKL contribute to cytosolic necrosome for... | KEEP AS NON CORE | Summary: IDA annotation of nuclear localization. Reason: RIPK3 shuttles between nucleus and cytoplasm and can be activated in the nucleus before export; however its necroptotic function is executed by cytosolic necrosomes, so nucleus is a non-core location. Supporting Evidence: PMID:30271893 We report that RIPK3 and MLKL continuously shuttle between the nucleus and the cytoplasm PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IEA annotation of nuclear localization. Reason: RIPK3 shuttles between nucleus and cytoplasm and can be activated in the nucleus before export; however its necroptotic function is executed by cytosolic necrosomes, so nucleus is a non-core location. Supporting Evidence: PMID:30271893 We report that RIPK3 and MLKL continuously shuttle between the nucleus and the cytoplasm PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation of nuclear localization. Reason: RIPK3 shuttles between nucleus and cytoplasm and can be activated in the nucleus before export; however its necroptotic function is executed by cytosolic necrosomes, so nucleus is a non-core location. Supporting Evidence: PMID:30271893 We report that RIPK3 and MLKL continuously shuttle between the nucleus and the cytoplasm PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation of cytoplasm. Reason: RIPK3 is predominantly cytoplasmic/cytosolic, where the necrosome forms. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation of cytoplasm. Reason: RIPK3 is predominantly cytoplasmic/cytosolic, where the necrosome forms. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | IDA PMID:22265413 Mixed lineage kinase domain-like protein mediates necrosis s... | ACCEPT | Summary: IDA: RIP3 forms cytoplasmic punctae (necrosomes) during necrosis. Reason: RIPK3 acts in cytosolic necrosome punctae; cytosol is the core location. Supporting Evidence: PMID:22265413 Treating cells with necrosulfonamide or knocking down MLKL expression arrested necrosis at a specific step at which RIP3 formed discrete punctae in cells. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: IEA cytosol annotation (GO_REF:0000044). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1810457 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-1810457). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2569057 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-2569057). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5213462 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-5213462). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5213464 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-5213464). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5213466 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-5213466). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5218891 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-5218891). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5218905 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-5218905). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5218906 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-5218906). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5357927 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-5357927). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5620975 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-5620975). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9013963 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9013963). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9686336 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9686336). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9686338 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9686338). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9686345 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9686345). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9686920 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9686920). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9686922 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9686922). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9686930 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9686930). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9687455 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9687455). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9687625 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9687625). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9687638 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9687638). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9687828 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9687828). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9688456 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9688456). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9688459 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9688459). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9688831 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9688831). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9688832 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9688832). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9688838 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9688838). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9693978 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9693978). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9793444 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9793444). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9793451 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9793451). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9793472 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9793472). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9793485 | ACCEPT | Summary: TAS cytosol annotation (Reactome:R-HSA-9793485). Reason: RIPK3 functions in the cytosol, where RIPK1-RIPK3 necrosomes assemble and phosphorylate MLKL. The specific Reactome reaction cited is one of many cytosolic necroptosis-pathway reactions in which RIPK3 participates. Supporting Evidence: PMID:30271893 Following necroptosis induction, RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. |
| GO:0007165 signal transduction | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation of signal transduction. Reason: Correct but very general; RIPK3's signaling role is specifically captured by necroptotic signaling pathway (GO:0097527). Supporting Evidence: PMID:22265413 The receptor-interacting serine-threonine kinase 3 (RIP3) is a key signaling molecule in the programmed necrosis (necroptosis) pathway. |
| GO:0007165 signal transduction | TAS PMID:10339433 Identification of RIP3, a RIP-like kinase that activates apo... | KEEP AS NON CORE | Summary: TAS annotation of signal transduction. Reason: Correct but very general; RIPK3's signaling role is specifically captured by necroptotic signaling pathway (GO:0097527). Supporting Evidence: PMID:10339433 Therefore, RIP3 appears to function as an intermediary in TNFalpha-induced apoptosis. |
| GO:0010468 regulation of gene expression | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA machine-learning inference of regulation of gene expression. Reason: Too broad and not reflecting a direct RIPK3 activity; any gene-expression effects (e.g. inflammatory cytokine output) are downstream of necroptotic signaling. |
| GO:0032147 activation of protein kinase activity | IMP PMID:22817896 The RIP1/RIP3 necrosome forms a functional amyloid signaling... | KEEP AS NON CORE | Summary: IMP: RHIM-mediated assembly is required for RIP1/RIP3 kinase activation. Reason: RIPK3 RHIM assembly drives activation of RIPK3 itself and RIPK1 within the necrosome. This is part of the necrosome-assembly mechanism (better captured by GO:1901026) rather than a separate regulatory function. Supporting Evidence: PMID:22817896 Mutations in the RHIMs of RIP1 and RIP3 that are defective in the interaction compromise cluster formation, kinase activation, and programmed necrosis in vivo. |
| GO:0032649 regulation of type II interferon production | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'regulation of type II interferon production'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0032649 regulation of type II interferon production | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'regulation of type II interferon production'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0032991 protein-containing complex | IDA PMID:22817896 The RIP1/RIP3 necrosome forms a functional amyloid signaling... | MODIFY | Summary: IDA: RIPK3 is part of the RIP1/RIP3 necrosome complex. Reason: The generic protein-containing complex term should be replaced by the specific complex, ripoptosome (GO:0097342; synonym necrosome), as already annotated by EXP from PMID:29681455. Proposed replacements: ripoptosome Supporting Evidence: PMID:22817896 The endogenous RIP1/RIP3 complex isolated from necrotic cells binds ThT, is ultrastable, and has a fibrillar core structure |
| GO:0033077 T cell differentiation in thymus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'T cell differentiation in thymus'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0033077 T cell differentiation in thymus | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'T cell differentiation in thymus'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0035556 intracellular signal transduction | IDA PMID:21931591 cIAP1/2 are direct E3 ligases conjugating diverse types of u... | KEEP AS NON CORE | Summary: IDA annotation of intracellular signal transduction. Reason: Correct but general. PMID:21931591 addresses cIAP-mediated ubiquitination and RIP3-dependent NF-kappaB activation, which the authors themselves describe as weak; the specific signaling role of RIPK3 is necroptotic signaling (GO:0097527). Supporting Evidence: PMID:21931591 Because RIP3 is a weak inducer of NF-ΞΊB |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation of intracellular signal transduction. Reason: Correct but general. PMID:21931591 addresses cIAP-mediated ubiquitination and RIP3-dependent NF-kappaB activation, which the authors themselves describe as weak; the specific signaling role of RIPK3 is necroptotic signaling (GO:0097527). |
| GO:0042802 identical protein binding | EXP PMID:36870681 NMR characterization of an assembling RHIM (RIP homotypic in... | ACCEPT | Summary: EXP: NMR characterization of RIPK3 RHIM self-assembly into amyloid. Reason: RIPK3 RHIM self-associates to form homo-amyloid fibrils, which underlie RIPK3 polymerization and activation; identical protein binding is an appropriate MF for this self-assembly. Supporting Evidence: PMID:36870681 Our results establish that the RHIM of RIPK3 is an intrinsically disordered protein motif PMID:33790016 polymerizes in response to the upstream signals |
| GO:0042802 identical protein binding | IPI PMID:22817896 The RIP1/RIP3 necrosome forms a functional amyloid signaling... | ACCEPT | Summary: IPI from the necrosome amyloid paper (abstract-only in cache). Reason: The cached abstract describes RIP1/RIP3 hetero-assembly; the curator presumably saw RIP3 self-association in the full text, which is consistent with later structural work showing RIPK3 RHIM homo-amyloid. Accepted, deferring to the curator. Supporting Evidence: PMID:22817896 Here, we report that the RIP homotypic interaction motifs (RHIMs) of RIP1 and RIP3 mediate the assembly of heterodimeric filamentous structures. PMID:33790016 polymerizes in response to the upstream signals |
| GO:0042981 regulation of apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse-derived transfer of regulation of apoptotic process. Reason: RIPK3 can influence apoptosis (early overexpression studies; in some contexts RIPK3 scaffolds caspase-8 activation), but its defining role is in necroptosis; loss of RIP3 disables necroptosis without affecting apoptosis in the ripoptosome context. Supporting Evidence: PMID:10358032 Overexpression studies revealed RIP3 to be a potent inducer of apoptosis PMID:21737330 Thus, loss of RIP3 disables TLR3-mediated necroptosis without affecting the apoptotic response |
| GO:0042981 regulation of apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse-derived transfer of regulation of apoptotic process. Reason: RIPK3 can influence apoptosis (early overexpression studies; in some contexts RIPK3 scaffolds caspase-8 activation), but its defining role is in necroptosis; loss of RIP3 disables necroptosis without affecting apoptosis in the ripoptosome context. Supporting Evidence: PMID:10358032 Overexpression studies revealed RIP3 to be a potent inducer of apoptosis PMID:21737330 Thus, loss of RIP3 disables TLR3-mediated necroptosis without affecting the apoptotic response |
| GO:0043029 T cell homeostasis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'T cell homeostasis'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0043029 T cell homeostasis | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'T cell homeostasis'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0044877 protein-containing complex binding | IMP PMID:22265414 The mitochondrial phosphatase PGAM5 functions at the converg... | KEEP AS NON CORE | Summary: IMP from the PGAM5 paper (abstract-only in cache). Reason: Binding of RIPK3 to necrosis-specific RIP1/RIP3/PGAM5-containing complexes is plausible from the abstract, but 'protein-containing complex binding' is uninformative and the full text was not available to verify the specific experiment. Kept as non-core rather than removed. Supporting Evidence: PMID:22265414 We report the identification of RIP1- and RIP3-containing protein complexes that form specifically in response to necrosis induction. |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000108 | REMOVE | Summary: Inter-ontology (GO_REF:0000108) inference of positive regulation of DNA-templated transcription, derived from the transcription coactivator activity annotation. Reason: This IEA is a mechanical consequence of the unsupported transcription coactivator activity annotation (also proposed for removal). RIPK3 is a cytosolic necroptotic kinase, not a transcriptional regulator. Supporting Evidence: PMID:10339433 The carboxy-terminal domain of RIP3, like that of RIP, could activate the transcription factor NFkappaB and induce apoptosis when expressed in mammalian cells. |
| GO:0046006 regulation of activated T cell proliferation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'regulation of activated T cell proliferation'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0046006 regulation of activated T cell proliferation | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'regulation of activated T cell proliferation'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0048535 lymph node development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'lymph node development'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0048535 lymph node development | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'lymph node development'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0048536 spleen development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'spleen development'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0048536 spleen development | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'spleen development'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0048538 thymus development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'thymus development'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0048538 thymus development | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'thymus development'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0051607 defense response to virus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA ortholog transfer of defense response to virus from mouse. Reason: RIPK3-dependent necroptosis is an antiviral defense (vaccinia control impaired in Rip3-/- mice), and herpesviruses encode RHIM inhibitors of RIPK3; this is a genuine but downstream physiological role of the necroptotic kinase. Supporting Evidence: PMID:19524513 Consequently, RIP3(-/-) mice exhibited severely impaired virus-induced tissue necrosis, inflammation, and control of viral replication. PMID:26559832 The RHIM domain of R1 was essential for its association with human RIP3 and RIP1, leading to disruption of the RIP1/RIP3 complex. |
| GO:0051607 defense response to virus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS ortholog transfer of defense response to virus from mouse. Reason: RIPK3-dependent necroptosis is an antiviral defense (vaccinia control impaired in Rip3-/- mice), and herpesviruses encode RHIM inhibitors of RIPK3; this is a genuine but downstream physiological role of the necroptotic kinase. Supporting Evidence: PMID:19524513 Consequently, RIP3(-/-) mice exhibited severely impaired virus-induced tissue necrosis, inflammation, and control of viral replication. PMID:26559832 The RHIM domain of R1 was essential for its association with human RIP3 and RIP1, leading to disruption of the RIP1/RIP3 complex. |
| GO:0060545 positive regulation of necroptotic process | IDA PMID:22265414 The mitochondrial phosphatase PGAM5 functions at the converg... | ACCEPT | Summary: IDA annotation of positive regulation of necroptotic process (PMID:22265414). Reason: RIPK3 is required for and drives necroptosis through its kinase activity; this regulatory annotation is consistent with its core role (also captured by necroptotic signaling pathway and necroptotic process). Supporting Evidence: PMID:22265414 The programmed necrosis induced by TNF-Ξ± requires the activities of the receptor-interacting serine-threonine kinases RIP1 and RIP3 and their interaction with the mixed lineage kinase domain-like protein MLKL. |
| GO:0060545 positive regulation of necroptotic process | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation of positive regulation of necroptotic process (GO_REF:0000120). Reason: RIPK3 is required for and drives necroptosis through its kinase activity; this regulatory annotation is consistent with its core role (also captured by necroptotic signaling pathway and necroptotic process). Supporting Evidence: PMID:19524512 The kinase activity of RIP3 is essential for necrosis execution. |
| GO:0060545 positive regulation of necroptotic process | IMP PMID:22817896 The RIP1/RIP3 necrosome forms a functional amyloid signaling... | ACCEPT | Summary: IMP annotation of positive regulation of necroptotic process (PMID:22817896). Reason: RIPK3 is required for and drives necroptosis through its kinase activity; this regulatory annotation is consistent with its core role (also captured by necroptotic signaling pathway and necroptotic process). Supporting Evidence: PMID:22817896 Mutations in the RHIMs of RIP1 and RIP3 that are defective in the interaction compromise cluster formation, kinase activation, and programmed necrosis in vivo. |
| GO:0070235 regulation of activation-induced cell death of T cells | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'regulation of activation-induced cell death of T cells'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0070235 regulation of activation-induced cell death of T cells | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'regulation of activation-induced cell death of T cells'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:0070266 necroptotic process | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation of necroptotic process (GO_REF:0000120). Reason: Core process. RIPK3 is the essential kinase of necroptosis: it is recruited into the RIPK1-RIPK3 necrosome and phosphorylates MLKL to trigger necroptotic death. Supporting Evidence: PMID:19524512 A genome wide siRNA screen revealed another member of the RIP kinase family, RIP3, to be required for necrosis. PMID:19524512 The kinase activity of RIP3 is essential for necrosis execution. |
| GO:0070266 necroptotic process | IMP PMID:21737330 cIAPs block Ripoptosome formation, a RIP1/caspase-8 containi... | ACCEPT | Summary: IMP annotation of necroptotic process (PMID:21737330). Reason: Core process. RIPK3 is the essential kinase of necroptosis: it is recruited into the RIPK1-RIPK3 necrosome and phosphorylates MLKL to trigger necroptotic death. Supporting Evidence: PMID:21737330 Thus, loss of RIP3 disables TLR3-mediated necroptosis without affecting the apoptotic response |
| GO:0070266 necroptotic process | IMP PMID:22817896 The RIP1/RIP3 necrosome forms a functional amyloid signaling... | ACCEPT | Summary: IMP annotation of necroptotic process (PMID:22817896). Reason: Core process. RIPK3 is the essential kinase of necroptosis: it is recruited into the RIPK1-RIPK3 necrosome and phosphorylates MLKL to trigger necroptotic death. Supporting Evidence: PMID:22817896 Mutations in the RHIMs of RIP1 and RIP3 that are defective in the interaction compromise cluster formation, kinase activation, and programmed necrosis in vivo. |
| GO:0070266 necroptotic process | IMP PMID:29883609 PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylat... | ACCEPT | Summary: IMP annotation of necroptotic process (PMID:29883609). Reason: Core process. RIPK3 is the essential kinase of necroptosis: it is recruited into the RIPK1-RIPK3 necrosome and phosphorylates MLKL to trigger necroptotic death. Supporting Evidence: PMID:29883609 This same phosphorylation event is also important for RIP3 kinase activity; thus, PELI1 preferentially targets kinase-active RIP3 for degradation. |
| GO:0070266 necroptotic process | TAS Reactome:R-HSA-5213460 | ACCEPT | Summary: TAS annotation of necroptotic process (Reactome:R-HSA-5213460). Reason: Core process. RIPK3 is the essential kinase of necroptosis: it is recruited into the RIPK1-RIPK3 necrosome and phosphorylates MLKL to trigger necroptotic death. Supporting Evidence: Reactome:R-HSA-5213460 The kinase activities of RIPK1 and RIPK3 are essential for the necroptotic cell death in human, mouse cell lines and genetic mice models |
| GO:0070301 cellular response to hydrogen peroxide | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Mouse-derived ortholog transfer of cellular response to hydrogen peroxide. Reason: Oxidative stimuli can engage RIPK3-dependent necrosis in some cell types, but this is a context-dependent response rather than a defined RIPK3 activity; human evidence indicates ROS-induced necrosis can proceed through PGAM5 independently of RIP3. Supporting Evidence: PMID:22265414 We report the identification of RIP1- and RIP3-containing protein complexes that form specifically in response to necrosis induction. |
| GO:0070301 cellular response to hydrogen peroxide | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Mouse-derived ortholog transfer of cellular response to hydrogen peroxide. Reason: Oxidative stimuli can engage RIPK3-dependent necrosis in some cell types, but this is a context-dependent response rather than a defined RIPK3 activity; human evidence indicates ROS-induced necrosis can proceed through PGAM5 independently of RIP3. Supporting Evidence: PMID:22265414 We report the identification of RIP1- and RIP3-containing protein complexes that form specifically in response to necrosis induction. |
| GO:0097190 apoptotic signaling pathway | TAS PMID:10339433 Identification of RIP3, a RIP-like kinase that activates apo... | KEEP AS NON CORE | Summary: TAS from the RIP3 cloning paper on apoptosis induction. Reason: Based on overexpression of the RIP3 C-terminus, which induced apoptosis independently of the kinase domain. RIPK3 can contribute to apoptotic signaling in some contexts, but this is not its core function. Supporting Evidence: PMID:10339433 The carboxy-terminal domain of RIP3, like that of RIP, could activate the transcription factor NFkappaB and induce apoptosis when expressed in mammalian cells. PMID:10339433 As with RIP and RIP2, the kinase domain of RIP3 was not required for either NFkappaB activation or apoptosis induction. |
| GO:0097300 programmed necrotic cell death | IEA GO_REF:0000107 | MODIFY | Summary: IEA transfer of programmed necrotic cell death. Reason: Correct but general; the specific programmed necrosis RIPK3 mediates is necroptosis (GO:0070266). Proposed replacements: necroptotic process Supporting Evidence: PMID:19524512 A genome wide siRNA screen revealed another member of the RIP kinase family, RIP3, to be required for necrosis. |
| GO:0097300 programmed necrotic cell death | ISS GO_REF:0000024 | MODIFY | Summary: ISS transfer of programmed necrotic cell death. Reason: Correct but general; the specific programmed necrosis RIPK3 mediates is necroptosis (GO:0070266). Proposed replacements: necroptotic process Supporting Evidence: PMID:19524512 A genome wide siRNA screen revealed another member of the RIP kinase family, RIP3, to be required for necrosis. |
| GO:0097342 ripoptosome | EXP PMID:29681455 The Structure of the Necrosome RIPK1-RIPK3 Core, a Human Het... | ACCEPT | Summary: EXP: structure of the human RIPK1-RIPK3 necrosome hetero-amyloid core (necrosome = ripoptosome in GO). Reason: Core complex. RIPK3 is an obligate structural and catalytic subunit of the necrosome (GO:0097342 ripoptosome, synonym necrosome). Supporting Evidence: PMID:29681455 The RIPK1-RIPK3 necrosome is an amyloid signaling complex that initiates TNF-induced necroptosis PMID:29681455 RIPK1 and RIPK3 alternately stack |
| GO:0097527 necroptotic signaling pathway | IMP PMID:22265413 Mixed lineage kinase domain-like protein mediates necrosis s... | ACCEPT | Summary: IMP annotation of necroptotic signaling pathway (PMID:22265413). Reason: Core process. RIPK3 is the central signaling kinase of the necroptosis pathway, linking RHIM-mediated necrosome assembly to MLKL phosphorylation. Supporting Evidence: PMID:22265413 MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. PMID:22265413 The receptor-interacting serine-threonine kinase 3 (RIP3) is a key signaling molecule in the programmed necrosis (necroptosis) pathway. |
| GO:0097527 necroptotic signaling pathway | IMP PMID:22817896 The RIP1/RIP3 necrosome forms a functional amyloid signaling... | ACCEPT | Summary: IMP annotation of necroptotic signaling pathway (PMID:22817896). Reason: Core process. RIPK3 is the central signaling kinase of the necroptosis pathway, linking RHIM-mediated necrosome assembly to MLKL phosphorylation. Supporting Evidence: PMID:22817896 Mutations in the RHIMs of RIP1 and RIP3 that are defective in the interaction compromise cluster formation, kinase activation, and programmed necrosis in vivo. |
| GO:0097528 execution phase of necroptosis | IEA GO_REF:0000107 | MODIFY | Summary: IEA transfer of execution phase of necroptosis. Reason: RIPK3 acts upstream of the execution phase: it phosphorylates MLKL, which then oligomerizes and permeabilizes the plasma membrane. RIPK3 is better described as acting in necroptotic signaling pathway (GO:0097527). Proposed replacements: necroptotic signaling pathway Supporting Evidence: PMID:22265413 MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. |
| GO:0097528 execution phase of necroptosis | ISS GO_REF:0000024 | MODIFY | Summary: ISS transfer of execution phase of necroptosis. Reason: RIPK3 acts upstream of the execution phase: it phosphorylates MLKL, which then oligomerizes and permeabilizes the plasma membrane. RIPK3 is better described as acting in necroptotic signaling pathway (GO:0097527). Proposed replacements: necroptotic signaling pathway Supporting Evidence: PMID:22265413 MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. |
| GO:0106310 protein serine kinase activity | EXP PMID:19524513 Phosphorylation-driven assembly of the RIP1-RIP3 complex reg... | MODIFY | Summary: EXP annotation of protein serine kinase activity (PMID:19524513). Reason: RIPK3 phosphorylates both threonine and serine residues (MLKL T357/S358; RIPK1/RIPK3 auto- and trans-phosphorylation), so the dual-specificity serine/threonine term GO:0004674 is the appropriate MF rather than the serine-only term. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: PMID:22265413 MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. |
| GO:0106310 protein serine kinase activity | EXP PMID:22265413 Mixed lineage kinase domain-like protein mediates necrosis s... | MODIFY | Summary: EXP annotation of protein serine kinase activity (PMID:22265413). Reason: RIPK3 phosphorylates both threonine and serine residues (MLKL T357/S358; RIPK1/RIPK3 auto- and trans-phosphorylation), so the dual-specificity serine/threonine term GO:0004674 is the appropriate MF rather than the serine-only term. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: PMID:22265413 MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000120 | MODIFY | Summary: IEA annotation of protein serine kinase activity (GO_REF:0000120). Reason: RIPK3 phosphorylates both threonine and serine residues (MLKL T357/S358; RIPK1/RIPK3 auto- and trans-phosphorylation), so the dual-specificity serine/threonine term GO:0004674 is the appropriate MF rather than the serine-only term. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: PMID:22265413 MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. |
| GO:0120283 protein serine/threonine kinase binding | EXP PMID:29681455 The Structure of the Necrosome RIPK1-RIPK3 Core, a Human Het... | ACCEPT | Summary: EXP annotation of binding to the serine/threonine kinase RIPK1 (PMID:29681455). Reason: RIPK3 binds RIPK1 via RHIM-RHIM hetero-amyloid interactions to form the necrosome; this specific kinase-kinase binding is central to necroptotic signaling. Supporting Evidence: PMID:29681455 The RIPK1-RIPK3 necrosome is an amyloid signaling complex that initiates TNF-induced necroptosis PMID:29681455 RIPK1 and RIPK3 alternately stack |
| GO:0120283 protein serine/threonine kinase binding | IPI PMID:22817896 The RIP1/RIP3 necrosome forms a functional amyloid signaling... | ACCEPT | Summary: IPI annotation of binding to the serine/threonine kinase RIPK1 (PMID:22817896). Reason: RIPK3 binds RIPK1 via RHIM-RHIM hetero-amyloid interactions to form the necrosome; this specific kinase-kinase binding is central to necroptotic signaling. Supporting Evidence: PMID:22817896 Here, we report that the RIP homotypic interaction motifs (RHIMs) of RIP1 and RIP3 mediate the assembly of heterodimeric filamentous structures. |
| GO:1901026 ripoptosome assembly involved in necroptotic process | IMP PMID:22817896 The RIP1/RIP3 necrosome forms a functional amyloid signaling... | ACCEPT | Summary: IMP: RHIM mutations block RIP1/RIP3 necrosome assembly and necroptosis. Reason: Core process. RIPK3 RHIM directly builds the necrosome (ripoptosome) hetero-amyloid scaffold required for necroptosis. Supporting Evidence: PMID:22817896 Here, we report that the RIP homotypic interaction motifs (RHIMs) of RIP1 and RIP3 mediate the assembly of heterodimeric filamentous structures. PMID:22817896 Mutations in the RHIMs of RIP1 and RIP3 that are defective in the interaction compromise cluster formation, kinase activation, and programmed necrosis in vivo. |
| GO:1990000 amyloid fibril formation | EXP PMID:22817896 The RIP1/RIP3 necrosome forms a functional amyloid signaling... | ACCEPT | Summary: EXP annotation of amyloid fibril formation (PMID:22817896). Reason: RIPK3 RHIM forms functional amyloid fibrils (hetero-amyloid with RIPK1 and homo-amyloid) that constitute the necrosome scaffold; this is a direct, physiological activity of RIPK3, not pathological aggregation. Supporting Evidence: PMID:22817896 Here, we report that the RIP homotypic interaction motifs (RHIMs) of RIP1 and RIP3 mediate the assembly of heterodimeric filamentous structures. PMID:22817896 The fibrils exhibit classical characteristics of Ξ²-amyloids |
| GO:1990000 amyloid fibril formation | IDA PMID:33790016 The structure of a minimum amyloid fibril core formed by nec... | ACCEPT | Summary: IDA annotation of amyloid fibril formation (PMID:33790016). Reason: RIPK3 RHIM forms functional amyloid fibrils (hetero-amyloid with RIPK1 and homo-amyloid) that constitute the necrosome scaffold; this is a direct, physiological activity of RIPK3, not pathological aggregation. Supporting Evidence: PMID:33790016 polymerizes in response to the upstream signals |
| GO:1990000 amyloid fibril formation | IMP PMID:22817896 The RIP1/RIP3 necrosome forms a functional amyloid signaling... | ACCEPT | Summary: IMP annotation of amyloid fibril formation (PMID:22817896). Reason: RIPK3 RHIM forms functional amyloid fibrils (hetero-amyloid with RIPK1 and homo-amyloid) that constitute the necrosome scaffold; this is a direct, physiological activity of RIPK3, not pathological aggregation. Supporting Evidence: PMID:22817896 Here, we report that the RIP homotypic interaction motifs (RHIMs) of RIP1 and RIP3 mediate the assembly of heterodimeric filamentous structures. PMID:22817896 The fibrils exhibit classical characteristics of Ξ²-amyloids |
| GO:2000379 positive regulation of reactive oxygen species metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse-derived transfer of positive regulation of ROS metabolic process. Reason: Necrosome activation triggers downstream ROS production, so the annotation has some support, but ROS generation is a downstream consequence of necroptotic signaling rather than a core RIPK3 function. Supporting Evidence: PMID:19524513 The phosphorylation of RIP1 and RIP3 stabilizes their association within the pronecrotic complex, activates the pronecrotic kinase activity, and triggers downstream reactive oxygen species production. |
| GO:2000452 regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
| GO:2000452 regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Electronic/ISS transfer from mouse Ripk3 of 'regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation'. Reason: This is a mouse-to-human ortholog transfer (Ensembl Compara IEA or curator ISS from mouse Ripk3, Q9QZL0). Immune and lymphoid phenotypes of this kind in mice are best explained as indirect consequences of RIPK3-dependent necroptotic cell death (for example, lymphoaccumulation and T cell abnormalities when necroptosis is unleashed by loss of caspase-8/FADD), not as a distinct activity of RIPK3 within the named process. RIPK3's own molecular role is that of the necroptotic kinase acting on MLKL and RIPK1. |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: Should RHIM-driven RIPK3 homo- and hetero-amyloid assembly be represented by a dedicated MF term (e.g. a signaling-scaffold or amyloid-forming activity) rather than through protein binding and amyloid fibril formation process terms?
Suggested experts: GO molecular function editors, necroptosis structural biologists
Q: Is the necrosome adequately represented in GO by GO:0097342 ripoptosome (necrosome as a synonym), given that the ripoptosome was originally defined as a RIPK1/FADD/caspase-8 platform that can signal apoptosis or necroptosis?
Suggested experts: GO cellular component editors
Q: Which mouse immune phenotypes transferred to human RIPK3 (lymphoid organ development, T cell homeostasis, cytotoxicity) reflect RIPK3 activity per se rather than unleashed necroptosis in Casp8/Fadd-deficient backgrounds?
Suggested experts: immunologists studying cell death in lymphocytes
Experiment: Determine the functional significance of nuclear RIPK3 activation by comparing necroptosis kinetics and MLKL phosphorylation in human cells expressing nuclear-export-defective versus nuclear-import-defective RIPK3.
Hypothesis: Nuclear activation of RIPK3 accelerates, but is not required for, cytosolic necrosome formation.
Type: cell-based localization mutant rescue
Experiment: Map additional bona fide RIPK3 substrates beyond MLKL and RIPK1 in human necroptotic cells using kinase-dead and analog-sensitive RIPK3 with quantitative phosphoproteomics.
Hypothesis: RIPK3 has few direct substrates and MLKL phosphorylation accounts for its necroptotic output.
Type: chemical-genetic phosphoproteomics
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)