{"gene":"RIPK1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2019,"finding":"Caspase-8 cleaves RIPK1 at Asp325 (mouse) / Asp324 (human) to limit apoptosis and necroptosis. Knock-in mice expressing RIPK1(D325A), which cannot be cleaved by caspase-8, die mid-gestation from TNF- and RIPK1-kinase-activity-dependent cell death involving FADD-caspase-8. Lethality was prevented by loss of TNFR1 or combined loss of MLKL and FADD, but not by loss of MLKL alone, demonstrating that cleavage of RIPK1 by caspase-8 dismantles death-inducing complexes.","method":"Knock-in mouse models (RIPK1-D325A, caspase-8 catalytic mutants, MLKL-KO, FADD-KO, TNFR1-KO); embryo histology; genetic epistasis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal knock-in and knockout mouse models with clear genetic epistasis; replicated across two independent Nature papers (PMID 31511692, 31827281)","pmids":["31511692"],"is_preprint":false},{"year":2019,"finding":"Heterozygous missense mutations D324N, D324H, and D324Y in human RIPK1 prevent caspase-8 cleavage, sensitizing cells to RIPK1-kinase-dependent apoptosis and necroptosis induced by TNF and causing an early-onset autoinflammatory periodic fever syndrome. Mouse knock-in Ripk1(D325A/D325A) embryonic lethality was rescued by combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone; loss of RIPK1 kinase activity also prevented lethality.","method":"Human genetic sequencing; knock-in mouse models (Ripk1D325A); cell death assays in patient-derived PBMCs and fibroblasts; genetic epistasis with Ripk3, Mlkl, Casp8 deletions","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — two independent papers (PMID 31827281, 31827280) with human genetics plus complementary mouse knock-in models and multiple orthogonal rescue experiments","pmids":["31827281","31827280"],"is_preprint":false},{"year":2016,"finding":"The RHIM domain of RIPK1 suppresses ZBP1-mediated activation of RIPK3-MLKL necroptosis. Mice with RHIM-mutant RIPK1 (IQIG→AAAA) died perinatally due to RIPK3/MLKL-dependent necroptosis; this lethality was prevented by ZBP1 deficiency, RIPK3 deficiency, or MLKL deficiency. ZBP1 interacted strongly with phospho-RIPK3 in RHIM-mutant cells but not in wild-type cells, demonstrating that the RIPK1 RHIM functions as a brake preventing ZBP1 from engaging RIPK3.","method":"Knock-in mouse models (RIPK1-RHIM mutant); genetic rescue with ZBP1-KO, RIPK3-KO, MLKL-KO; Co-immunoprecipitation of ZBP1–RIPK3 complex","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — two simultaneous independent Nature papers (PMID 27819681, 27819682) with knock-in mice, multiple genetic rescues, and Co-IP validation","pmids":["27819681","27819682"],"is_preprint":false},{"year":2016,"finding":"Optineurin (OPTN) actively suppresses RIPK1-dependent signaling by regulating RIPK1 turnover. Loss of OPTN in the CNS leads to progressive dysmyelination and axonal degeneration via engagement of RIPK1, RIPK3, and MLKL necroptotic machinery.","method":"OPTN-knockout mice; pharmacological RIPK1 inhibition; histopathology of human ALS samples; genetic rescue with RIPK1/RIPK3 deficiency","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mouse model plus pharmacological inhibition with defined cellular phenotype, corroborated in human ALS tissue","pmids":["27493188"],"is_preprint":false},{"year":2018,"finding":"TBK1 and IKKε phosphorylate RIPK1 within the TNFR1 signaling complex (TNFR1-SC) to prevent RIPK1-dependent cell death. LUBAC-generated linear (M1) ubiquitin enables recruitment and activation of TBK1 and IKKε at the TNFR1-SC via NEMO-TANK-NAP1 adaptors; this checkpoint is essential in vivo to prevent TNF-induced lethal shock.","method":"Biochemical reconstitution of TNFR1-SC; RIPK1 phosphorylation assays; TBK1/IKKε kinase-dead mutants; in vivo TNF shock model","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic phosphorylation assays, signaling complex reconstitution, and in vivo epistasis in a single rigorous study (PMID 30420664), independently supported by PMID 30146158","pmids":["30420664"],"is_preprint":false},{"year":2018,"finding":"TBK1 is an endogenous inhibitor of RIPK1: embryonic lethality of Tbk1-/- mice depends on RIPK1 kinase activity, placing TBK1 upstream of RIPK1 as a negative regulator. Reduced TAK1 expression in aging brains cooperates with TBK1 haploinsufficiency to promote RIPK1-driven ALS/FTD hallmarks.","method":"Tbk1-/- mice rescued by RIPK1 kinase inhibition; Tbk1+/- aged mice with genetic/pharmacological RIPK1 inhibition; epistasis with TAK1 expression","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models plus pharmacological inhibition with defined phenotypic rescue in a single comprehensive study","pmids":["30146158"],"is_preprint":false},{"year":2014,"finding":"RIPK1 both promotes and suppresses RIPK3 oligomerization. Chemically enforced oligomerization of RIPK3 is sufficient to induce necroptosis independent of RIPK1 activity; however, RIPK1 intrinsically suppresses spontaneous RIPK3 activation in the cytosol, as cells lacking RIPK1 show increased spontaneous RIPK3-dependent death, while catalytically inactive or inhibited RIPK1 protects against this death.","method":"Inducible dimerization/oligomerization RIPK3 constructs; RIPK1-KO and kinase-dead cells; necroptosis assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic and pharmacological tools, single lab, multiple orthogonal approaches","pmids":["24902904"],"is_preprint":false},{"year":2019,"finding":"Ubiquitination of RIPK1 at K376 is required to suppress RIPK1 kinase activity during embryogenesis. Mice expressing RIPK1(K376R) die during embryogenesis; lethality is fully rescued by combined deletion of Fadd and Ripk3 or Mlkl, and by RIPK1 kinase inhibitor treatment. K376R mutation promotes complex II formation and increases RIPK1 activation downstream of TNFR1.","method":"Knock-in mouse model (RIPK1-K376R); pharmacological RIPK1 kinase inhibitor; genetic rescue with Fadd/Ripk3/Mlkl/Tnfr1 deletion; immunoprecipitation of complex II","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — knock-in mouse with multiple genetic rescues and mechanistic complex II pulldown, two independent papers (PMID 31519886, 32999468) converging on same site","pmids":["31519886","32999468"],"is_preprint":false},{"year":2021,"finding":"OTUD1 deubiquitinase physically interacts with RIPK1 and selectively cleaves K63-linked polyubiquitin chains from RIPK1, thereby inhibiting recruitment of NEMO and suppressing NF-κB activation. Loss of OTUD1 promotes colonic inflammation via excessive RIPK1-mediated NF-κB signaling.","method":"Co-immunoprecipitation of OTUD1–RIPK1; ubiquitin linkage-specific deubiquitination assays; OTUD1-KO mice; bone marrow transplantation","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, biochemical ubiquitin assay, and in vivo mouse model in single lab","pmids":["34876703"],"is_preprint":false},{"year":2023,"finding":"AMPK phosphorylates RIPK1 at Ser415 to suppress energy-stress-induced RIPK1 activation and cell death. Inhibiting pS415-RIPK1 (via AMPK deficiency or RIPK1-S415A mutation) promotes RIPK1 activation. Genetic inactivation of RIPK1 protects against ischemic injury in myeloid Ampkα1-deficient mice, establishing AMPK as an upstream suppressor of RIPK1 in the metabolic checkpoint.","method":"In vitro kinase assays (AMPK phosphorylates RIPK1); knock-in RIPK1-S415A mice; Ampkα1-myeloid KO mice; ischemia model with genetic rescue","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro kinase assay plus knock-in mouse and in vivo ischemia model; single lab but multiple orthogonal methods","pmids":["37384704"],"is_preprint":false},{"year":2020,"finding":"ULK1 phosphorylates RIPK1 at multiple sites including Ser357 in the intermediate domain. ULK1-mediated phosphorylation reduces complex IIb/necrosome assembly and TNF-induced cell death; ULK1 depletion enhances TNF-induced cell death.","method":"In vitro kinase assay; mass spectrometry identification of ULK1 phosphorylation sites on RIPK1; siRNA knockdown; TNF-induced cell death assays; phosphomimetic mutants","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct in vitro kinase assay with site identification, single lab","pmids":["32320653"],"is_preprint":false},{"year":2022,"finding":"JAK1 and SRC (non-receptor tyrosine kinases) phosphorylate RIPK1 at Y384 (Y383 in mouse), suppressing TNF-induced cell death. Ripk1(Y383F/Y383F) knock-in mice develop systemic inflammation and emergency haematopoiesis; mechanistically, the Y383F mutation promotes RIPK1 kinase activation and impairs MK2 recruitment/activation. Inflammation is prevented by RIPK1 kinase inhibition or deletion of TNFR1 or RIPK3+Caspase8.","method":"In vitro kinase assay (JAK1/SRC phosphorylate RIPK1-Y384); knock-in mouse model (Ripk1-Y383F); genetic rescue; cell death assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct kinase assay plus knock-in mouse with multiple genetic rescues demonstrating in vivo relevance","pmids":["36329033"],"is_preprint":false},{"year":2023,"finding":"SENP1 (SUMO-specific protease) deSUMOylates RIPK1 within the TNF-RSC, keeping RIPK1 in check. Loss of SENP1 leads to SUMOylation of RIPK1, which re-orchestrates the TNF-RSC and modulates ubiquitination patterns and kinase activity of RIPK1, sensitizing cells to RIPK1-kinase-dependent apoptosis.","method":"Hepatocyte-specific SENP1-KO mice; RIPK1 SUMOylation assays; TNF-RSC immunoprecipitation; rescue by RIPK1 kinase-dead knockin","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical SUMOylation assay and Co-IP plus conditional KO mouse with RIPK1 kinase-dead rescue, single lab","pmids":["36414671"],"is_preprint":false},{"year":2023,"finding":"EGLN1-mediated prolyl hydroxylation of RIPK1 promotes its binding to pVHL, suppressing RIPK1 kinase activation under normoxic conditions. Prolonged hypoxia reduces prolyl hydroxylation of RIPK1, thereby promoting RIPK1 kinase activation and downstream cell death and inflammation independent of TNFα-TNFR1.","method":"Prolyl hydroxylation assays; pVHL co-immunoprecipitation; hepatocyte-specific Vhl-KO mice; EGLN1 inhibitor experiments; cell death assays under hypoxia","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical hydroxylation/binding assays plus conditional mouse KO, single lab","pmids":["37400498"],"is_preprint":false},{"year":2021,"finding":"PPP1R3G recruits protein phosphatase 1 gamma (PP1γ) to complex I to dephosphorylate inhibitory phosphorylation sites on RIPK1 (including Ser25), enabling RIPK1 kinase activation and cell death. PPP1R3G mutants unable to bind PP1γ fail to rescue RIPK1 activation; Ppp1r3g-/- mice are protected from TNF-induced SIRS.","method":"CRISPR whole-genome KO screen; Co-IP of PPP1R3G–PP1γ–RIPK1; PPP1R3G binding-mutant rescue; RIPK1-S25A mutation; Ppp1r3g-/- mice","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genome-wide screen plus biochemical validation with Co-IP, mutagenesis, in vivo mouse model; single lab but multiple orthogonal methods","pmids":["34862394"],"is_preprint":false},{"year":2022,"finding":"Activated nuclear RIPK1 physically associates with the BAF chromatin-remodeling complex. Upon RIPK1 activation, the RIPK1/BAF complex is recruited to active enhancers and promoters (marked by H3K4me1 and H3K27ac), where RIPK1 phosphorylates SMARCC2, a key BAF subunit, promoting chromatin remodeling and transcription of specific proinflammatory genes independent of cell death.","method":"Co-immunoprecipitation of nuclear RIPK1 with BAF; ChIP-seq for RIPK1 on H3K4me1/H3K27ac loci; phosphorylation assay for SMARCC2; nuclear fractionation; RIPK1 kinase inhibitor","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP-seq, and phosphorylation assay in single lab, novel nuclear function","pmids":["35661830"],"is_preprint":false},{"year":2020,"finding":"RIPK1 promotes mTORC1 inhibition during energetic stress by mediating the interaction between AMPK and TSC2 and facilitating TSC2 phosphorylation at Ser1387. RIPK1 loss results in high basal mTORC1 activity, defective lysosomes, and accumulation of RIPK3 and caspase-8, sensitizing cells to death under low glucose or metformin.","method":"Co-immunoprecipitation of RIPK1–AMPK–TSC2; TSC2 phosphorylation assays; mTORC1 activity measurement in RIPK1-deficient cells/mice; lysosome functional assays; genetic rescue by mTORC1 inhibition","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, biochemical phosphorylation, and cell/mouse phenotype, single lab","pmids":["33271062"],"is_preprint":false},{"year":2021,"finding":"The lysosomal Rag-Ragulator supercomplex licenses RIPK1-dependent caspase-8 activation and pyroptosis during Yersinia infection. FADD, RIPK1, and caspase-8 are recruited to Rag-Ragulator, causing RIPK1 phosphorylation and caspase-8 activation. This depends on Rag GTPase activity and lysosomal tethering but not mTORC1.","method":"Genome-wide CRISPR screen; Co-immunoprecipitation of FADD/RIPK1/caspase-8 with Rag-Ragulator; Rag GTPase mutants; lysosomal tethering mutants; caspase-8 activity assays","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — unbiased genome-wide CRISPR screen with mechanistic Co-IP and mutant validation, rigorous controls distinguishing from mTORC1","pmids":["35058659"],"is_preprint":false},{"year":2016,"finding":"Loss of RIPK1 in liver parenchymal cells (LPC) leads to TNF-dependent proteasomal degradation of TRAF2 in a kinase-independent manner, thereby activating caspase-8. Combined loss of RIPK1 and TRAF2 in LPC impairs NF-κB activation and promotes spontaneous hepatocellular carcinoma, establishing a RIPK1–TRAF2 tumor-suppressive axis.","method":"LPC-specific Ripk1/Traf2 conditional KO mice; TRAF2 ubiquitination/degradation assays; caspase-8 activity; TNF treatment; spontaneous tumor monitoring","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse models with biochemical validation of TRAF2 degradation and caspase-8 activation, single lab","pmids":["28017612"],"is_preprint":false},{"year":2017,"finding":"Kinase-independent functions of RIPK1 promote hepatocyte survival via cooperation with NF-κB/RelA signaling. Combined RIPK1 and RelA deficiency in liver parenchymal cells causes hepatocyte apoptosis and spontaneous chronic liver disease/cancer independent of TNFR1. RIPK1 kinase inactivity does not inhibit DEN-induced liver tumor formation, showing kinase-independent pro-tumorigenic RIPK1 scaffold function.","method":"LPC-specific Ripk1/RelA double conditional KO; kinase-dead RIPK1 knock-in mice; DEN-induced liver tumor models; genetic rescue with TNFR1 deletion","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple conditional KO mouse models with defined phenotype, single lab","pmids":["28628031"],"is_preprint":false},{"year":2016,"finding":"RIPK1 and RIPK3 kinase activities promote pro-inflammatory gene expression (sustained ERK, c-Fos, NF-κB activation) downstream of TLR4/LPS in macrophages, independent of their cell death functions. This regulation requires the adaptor TRIF and proceeds cell-autonomously; it accounts for acute LPS-induced inflammatory responses in vivo.","method":"Primary macrophage KO/kinase-inhibitor experiments; LPS stimulation with caspase-8 inhibition; in vivo LPS challenge with genetic/pharmacological RIPK1/RIPK3 inhibition; signaling pathway analysis","journal":"Immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and pharmacological tools with in vivo validation, single lab","pmids":["27396959"],"is_preprint":false},{"year":2024,"finding":"The RIPK1 death domain (DD) prevents ZBP1- and TRIF-mediated activation of RIPK3. A mutation disrupting the RIPK1 DD (R588E) caused perinatal lethality from ZBP1-mediated necroptosis, and postnatal inflammatory pathology via TNFR1/TRADD/TRIF-dependent RIPK3 signaling. Biochemically, ZBP1- and TRIF-mediated RIPK3 activation required RIPK1 kinase activity in wild-type cells but not in Ripk1(R588E) cells, indicating that DD-dependent RIPK1 oligomerization and FADD interaction gate the mechanism of RIPK3 activation.","method":"Knock-in mouse model (Ripk1-R588E); genetic rescue with ZBP1-KO, RIPK3-KO, MLKL-KO, TNFR1-KO, TRADD-KO; biochemical RIPK3 activation assays comparing WT vs R588E cells","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — knock-in mouse with multiple orthogonal genetic rescues and mechanistic biochemical assays distinguishing kinase-dependent vs DD-dependent pathways","pmids":["38744293"],"is_preprint":false},{"year":2024,"finding":"S-palmitoylation is a licensing post-translational modification for RIPK1 kinase. TNF induces DHHC5-mediated palmitoylation of RIPK1, which depends on K63-linked ubiquitination of RIPK1, promotes homo-interaction of the RIPK1 kinase domain, and enhances RIPK1 kinase activity and cell death when cell death checkpoints are disabled.","method":"Palmitoylation assays (acyl-RAC); DHHC5 KO and overexpression; K63-ubiquitination requirement tested by mutation; RIPK1 kinase domain interaction assays; cell death assays in murine NASH model","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct palmitoylation biochemical assays with mechanistic domain interaction studies and in vivo disease model, single lab","pmids":["39471814"],"is_preprint":false},{"year":2024,"finding":"PARP5A and RNF146 form liquid-like condensates via phase separation (recruited by TAX1BP1) to perform poly-ADP-ribosylation (PARylation) and PARylation-dependent ubiquitination (PARdU) of activated RIPK1. PARdU occurs predominantly at K376 of mouse RIPK1 and promotes proteasomal degradation of kinase-activated RIPK1, restraining necroptosis.","method":"Phase separation assays; PARylation assays; Co-IP of PARP5A/RNF146 with RIPK1; ubiquitination assays at K376; proteasome inhibitor experiments; necroptosis readouts in mouse embryonic fibroblasts","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct biochemical assays for PARylation and ubiquitination plus phase separation characterization, single lab","pmids":["38272024"],"is_preprint":false},{"year":2024,"finding":"UDP-glucuronate, produced by UGDH from UDP-glucose, directly binds to the kinase domain of RIPK1 and inhibits its activation. UGDH deficiency in hepatocytes promotes RIPK1-kinase-dependent apoptosis and NASH progression; recovering UDP-glucuronate levels suppresses liver damage even after disease onset.","method":"Direct binding assay (UDP-glucuronate to RIPK1 kinase domain); UGDH conditional KO mice; rescue by RIPK1 kinase-dead knockin; metabolomic measurements","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct binding assay plus KO mouse with genetic rescue, single lab","pmids":["37169760"],"is_preprint":false},{"year":2021,"finding":"PPP1R3G/PP1γ phosphatase promotes RIPK1-dependent apoptosis and necroptosis by dephosphorylating inhibitory phosphorylations of RIPK1 (including Ser25) within complex I. A PPP1R3G mutant that cannot bind PP1γ fails to rescue RIPK1 activation; Ppp1r3g-/- mice are protected from TNF-induced SIRS.","method":"CRISPR genome-wide KO screen; Co-IP; PP1γ-binding mutant; RIPK1 S25A mutation; Ppp1r3g-/- mice","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — unbiased screen, mechanistic Co-IP with mutagenesis, and in vivo validation","pmids":["34862394"],"is_preprint":false},{"year":2024,"finding":"The PP6 phosphatase holoenzyme (PPP6C catalytic subunit + PPP6R1/R2/R3 regulatory subunits) promotes RIPK1-dependent PANoptosis by enhancing pro-death autophosphorylation of RIPK1 at Ser166 and reducing pro-survival phosphorylation at Ser321. PP6 regulatory subunits act redundantly.","method":"CRISPR cell death screen; genetic knockdown/KO of PP6 components; Western blot for RIPK1 pS166/pS321; TAK1 inhibitor-induced PANoptosis assay","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen with biochemical phosphorylation validation, single lab","pmids":["38807188"],"is_preprint":false},{"year":2022,"finding":"When caspase-8 is deleted or inhibited, RIPK1 interacts with TBK1 to drive elevated type I IFN production. Combined deletion of caspase-8 and RIPK1 reduces type I IFN signaling, demonstrating that caspase-8 negatively regulates tonic IFN production by inhibiting the RIPK1-TBK1 axis.","method":"Caspase-8 KO/inhibitor experiments; Co-IP of RIPK1–TBK1; IFN production assays; combined caspase-8/RIPK1 double-KO mice","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and double-KO epistasis with IFN measurements, single lab","pmids":["36198273"],"is_preprint":false},{"year":2024,"finding":"In ZMPSTE24-deficient cells, accumulated farnesylated prelamin A recruits RIPK1 to the nucleus upon TNF stimulation, where kinase-activated RIPK1 promotes RIPK3-mediated MLKL activation at the nuclear envelope, leading to nuclear envelope disruption and necroptosis. Genetic inactivation of necroptosis ameliorates progeroid phenotypes in Zmpste24-/- mice.","method":"Nuclear fractionation and Co-IP of prelamin A–RIPK1; farnesylation inhibitor rescue; RIPK3/MLKL KO rescue in Zmpste24-/- mice; live-cell imaging of nuclear MLKL activation","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical nuclear Co-IP, farnesylation dependence, genetic rescue in KO mice, single lab","pmids":["38538837"],"is_preprint":false},{"year":2024,"finding":"Amyloid structure of mouse RIPK1 RHIM-containing domain (82-residue sequence) was determined by solid-state NMR, revealing an 'N'-shaped fibril subunit with four β-strands. The central β-strand is formed by the conserved IQIG tetrad. Upon mixing with RIPK3, RIPK1/RIPK3 complex fibrils form with altered structural rigidity, consistent with RHIM-mediated heterotypic amyloid interaction.","method":"Solid-state NMR; structural determination of RIPK1 RHIM amyloid; mixing experiments with RIPK3 to form heterotypic fibrils","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — solid-state NMR structural determination with functional domain mapping; single lab but rigorous structural method","pmids":["39143113"],"is_preprint":false},{"year":2023,"finding":"SMYD2 histone methyltransferase targets RIPK1 (non-histone substrate) and inhibits RIPK1 phosphorylation, thereby suppressing TNF-induced apoptosis and necroptosis in colon tumor cells. SMYD2 deficiency sensitizes tumor cells to TNF-induced cell death and impairs tumor growth in two independent murine cancer models.","method":"Co-IP of SMYD2–RIPK1; RIPK1 phosphorylation assays in SMYD2-deficient cells; SMYD2 pharmacological inhibition; in vivo tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and phosphorylation assays with in vivo tumor model validation, single lab","pmids":["35022391"],"is_preprint":false},{"year":2022,"finding":"In cancer cells, RIPK1 diverts TNF signaling through NF-κB and away from cell death via its ubiquitin scaffolding (non-kinase) function, promoting an immunosuppressive chemokine program that decreases T and NK cell infiltration. This RIPK1-mediated resistance to immune checkpoint blockade requires the scaffold but not kinase function.","method":"Genetic interaction screen in cancer cells; RIPK1 KO and reconstitution with scaffold vs kinase mutants; NF-κB and cell death assays; in vivo tumor-infiltrating lymphocyte analysis","journal":"Immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic screen with domain-specific rescue experiments and in vivo validation, single lab","pmids":["35417675"],"is_preprint":false},{"year":2024,"finding":"O-GlcNAcylation of RIPK1 at Ser331, Ser440, and Ser669 by OGT (which interacts with RIPK1 via its TPR domain) regulates RIPK1 ubiquitination and the formation of the RIPK1/FADD/Caspase-8 complex, thereby inhibiting sunitinib-induced RIPK1-dependent apoptosis in renal cell carcinoma.","method":"Co-IP of OGT–RIPK1; mass spectrometry identification of O-GlcNAcylation sites; site-specific mutation of Ser331/440/669; RIPK1/FADD/Caspase-8 complex pulldown; cell death assays","journal":"Drug resistance updates","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry site identification, Co-IP, and mutagenesis with functional assay, single lab","pmids":["39276723"],"is_preprint":false},{"year":2024,"finding":"Spermidine mediates acetylhypusination (a novel PTM combining acetylation with hypusine-like modification) of RIPK1, suppressing RIPK1 kinase-mediated cell death. NAT1 (murine) / NAT2 (human) deficiency reduces cellular spermidine levels, leading to loss of this suppressive modification on RIPK1 and promoting diabetic vascular pathology reversible by RIPK1 inhibition.","method":"Identification of acetylhypusination modification on RIPK1; spermidine supplementation rescue; NAT1-KO mice; RIPK1 inhibitor in vivo; human diabetic vascular tissue analysis","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — novel PTM biochemically identified with in vivo rescue and patient tissue validation, single lab","pmids":["39511379"],"is_preprint":false},{"year":2021,"finding":"RIPK1 deficiency in T cells causes premature senescence mediated by RIPK3 and caspase-8. Combined deficiency of RIPK3 and caspase-8 inhibition restores proliferative responses and reduces mTORC1 hyperactivation and senescence-related gene expression in RIPK1-deficient CD4 T cells, demonstrating that RIPK1 normally blocks RIPK3/caspase-8-mediated T cell senescence.","method":"T cell-specific RIPK1 conditional KO mice; combined RIPK3-KO and caspase-8 inhibition; mTORC1 activity measurement; senescence marker assays; proliferation assays","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mice with genetic double-rescue experiments; single lab","pmids":["36696505"],"is_preprint":false},{"year":2024,"finding":"RIPK1 forms a complex with JAK1 and RIPK3 to promote STAT1 activation in intestinal epithelial cells, driving MHC class II and chemokine expression that sustains alloreactive T cell responses in GVHD. Interferon-γ from alloreactive T cells amplifies this via JAK/STAT1-dependent enhancement of RIPK1/RIPK3 signaling, creating a feed-forward inflammatory cascade.","method":"Co-IP of RIPK1/RIPK3 with JAK1; STAT1 activation assays; IEC-specific RIPK3 conditional KO; JAK/STAT1 pathway analysis; allogeneic HSCT mouse model; selective RIPK1 inhibitor (Zharp1-211)","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, conditional KO, and pharmacological inhibition with in vivo GVHD model, single lab","pmids":["36356302"],"is_preprint":false}],"current_model":"RIPK1 is a multifunctional serine/threonine kinase that acts as a signaling node downstream of death receptors (primarily TNFR1), TLRs, and ZBP1: in its scaffold (kinase-inactive) form it promotes cell survival and NF-κB/MAPK inflammatory signaling, whereas kinase activation drives apoptosis, necroptosis, and transcriptional inflammation via chromatin remodeling; its activity is tightly controlled by multiple post-translational modifications—K63/linear ubiquitination at K376 (by cIAPs/LUBAC), inhibitory phosphorylation at Ser25 (by IKKα/β), Ser321 (by MK2), Ser415 (by AMPK), and Y384 (by JAK1/SRC), activating autophosphorylation at Ser166, prolyl hydroxylation (by EGLN1/pVHL), SUMOylation, palmitoylation, acetylhypusination, and O-GlcNAcylation—as well as caspase-8 cleavage at Asp325 that dismantles death complexes; the RHIM domain sequesters ZBP1 from activating RIPK3, and nuclear RIPK1 directly phosphorylates the BAF complex subunit SMARCC2 to drive proinflammatory gene transcription."},"narrative":{"mechanistic_narrative":"RIPK1 is a master signaling node downstream of TNFR1 and other innate immune receptors that integrates ubiquitin and phosphorylation signals to switch cells between survival, inflammation, and regulated death, with its kinase activity gating apoptosis and necroptosis while its scaffold function supports survival and NF-κB signaling [PMID:31519886, PMID:32999468, PMID:34862394, PMID:35417675]. A dense layer of post-translational modifications keeps RIPK1 kinase activity restrained as a default state: K63-linked ubiquitination at K376 suppresses complex II formation [PMID:31519886, PMID:32999468]; inhibitory phosphorylations placed by TBK1/IKKε within the TNFR1 signaling complex [PMID:30420664, PMID:30146158], by AMPK at Ser415 during energy stress [PMID:37384704], by ULK1 [PMID:32320653], and by JAK1/SRC at Y384 [PMID:36329033] each act as independent checkpoints, while removal of inhibitory phosphorylation by the PPP1R3G/PP1γ phosphatase at complex I (e.g. Ser25) and the PP6 holoenzyme (favoring autophosphorylation at Ser166 over Ser321) licenses RIPK1 activation and death [PMID:34862394, PMID:38807188]. Additional modifications—deSUMOylation by SENP1 [PMID:36414671], EGLN1-mediated prolyl hydroxylation enabling pVHL binding [PMID:37400498], DHHC5-dependent S-palmitoylation that drives kinase-domain self-association [PMID:39471814], PARylation-dependent ubiquitination by PARP5A/RNF146 targeting activated RIPK1 for degradation [PMID:38272024], O-GlcNAcylation by OGT [PMID:39276723], spermidine-dependent acetylhypusination [PMID:39511379], and the metabolite UDP-glucuronate binding the kinase domain [PMID:37169760]—collectively tune the activation threshold across metabolic and inflammatory contexts. Caspase-8 cleavage at Asp325/Asp324 dismantles death-inducing complexes, and loss of this cleavage causes lethal TNF/kinase-dependent cell death in mice and an autoinflammatory periodic fever syndrome in humans [PMID:31511692, PMID:31827281, PMID:31827280]. Independent of the kinase, the RIPK1 RHIM and death domains restrain ZBP1- and TRIF-driven RIPK3-MLKL necroptosis, the RHIM forming a heterotypic amyloid interface with RIPK3 [PMID:27819681, PMID:27819682, PMID:38744293, PMID:39143113]. Beyond cell death, RIPK1 drives transcriptional inflammation: activated nuclear RIPK1 associates with the BAF chromatin-remodeling complex and phosphorylates SMARCC2 to remodel enhancers and promoters of proinflammatory genes [PMID:35661830], and RIPK1/RIPK3 kinase activity sustains pro-inflammatory gene expression downstream of TLR4/TRIF [PMID:27396959]. RIPK1 also serves kinase-independent metabolic and survival roles, scaffolding AMPK–TSC2 to restrain mTORC1 [PMID:33271062] and cooperating with TRAF2 and NF-κB/RelA to maintain hepatocyte survival, where its loss promotes spontaneous liver cancer [PMID:28017612, PMID:28628031].","teleology":[{"year":2014,"claim":"Established that RIPK1 paradoxically both enables and restrains RIPK3-driven necroptosis, framing RIPK1 as a bidirectional regulator rather than a simple activator.","evidence":"Inducible RIPK3 oligomerization constructs in RIPK1-KO and kinase-dead cells with necroptosis assays","pmids":["24902904"],"confidence":"Medium","gaps":["Molecular basis for cytosolic suppression of spontaneous RIPK3 activation not resolved","Single-lab observation"]},{"year":2016,"claim":"Defined the RIPK1 RHIM as a brake that prevents ZBP1 from engaging RIPK3, explaining why RHIM-mutant mice die of necroptosis.","evidence":"RHIM-mutant knock-in mice with ZBP1/RIPK3/MLKL rescue and ZBP1–RIPK3 Co-IP","pmids":["27819681","27819682"],"confidence":"High","gaps":["Structural basis of RHIM-mediated sequestration not defined at this stage","Does not address how the brake is released physiologically"]},{"year":2016,"claim":"Identified upstream regulators of RIPK1 turnover (OPTN) and OTUD1-mediated K63-deubiquitination, and a kinase-independent RIPK1–TRAF2 tumor-suppressive axis in liver, broadening RIPK1 control beyond its catalytic activity.","evidence":"OPTN-KO and conditional Ripk1/Traf2 KO mice; ubiquitin-linkage-specific deubiquitination assays; TRAF2 degradation assays","pmids":["27493188","28017612","27396959"],"confidence":"Medium","gaps":["Mechanistic link between ubiquitin editing and complex II assembly incomplete","Tissue-specificity of survival vs death decisions unresolved"]},{"year":2018,"claim":"Placed TBK1/IKKε as LUBAC-dependent checkpoint kinases that phosphorylate RIPK1 in the TNFR1-SC, with TBK1 acting genetically upstream of RIPK1 to prevent lethal cell death and neurodegeneration.","evidence":"TNFR1-SC reconstitution, kinase-dead TBK1/IKKε mutants, Tbk1-/- mice rescued by RIPK1 kinase inhibition","pmids":["30420664","30146158"],"confidence":"High","gaps":["Precise inhibitory phosphosites placed by TBK1/IKKε not fully mapped here","Cooperation with other checkpoint kinases unclear"]},{"year":2019,"claim":"Showed that caspase-8 cleavage of RIPK1 at Asp325/324 dismantles death complexes, and that loss of this cleavage causes TNF/kinase-dependent lethality in mice and a human autoinflammatory disease.","evidence":"RIPK1-D325A knock-in mice with genetic epistasis; human sequencing of D324 mutations; patient-derived cell death assays","pmids":["31511692","31827281","31827280"],"confidence":"High","gaps":["How cleavage products redistribute signaling not detailed","Trigger that engages caspase-8 cleavage in homeostasis unclear"]},{"year":2019,"claim":"Demonstrated that K376 ubiquitination is required to suppress RIPK1 kinase activity during embryogenesis, linking a specific ubiquitin site to complex II restraint.","evidence":"RIPK1-K376R knock-in mice with Fadd/Ripk3/Mlkl rescue and complex II IP","pmids":["31519886","32999468"],"confidence":"High","gaps":["Identity of ligases/DUBs acting at K376 in vivo not fully assigned here","Ubiquitin linkage type at K376 not resolved in this work"]},{"year":2020,"claim":"Revealed kinase-independent metabolic scaffolding by RIPK1, bridging AMPK and TSC2 to restrain mTORC1 and maintain lysosomal homeostasis.","evidence":"Co-IP of RIPK1–AMPK–TSC2; TSC2 Ser1387 phosphorylation; mTORC1/lysosome assays in RIPK1-deficient cells","pmids":["33271062"],"confidence":"Medium","gaps":["Direct vs indirect role of RIPK1 in TSC2 phosphorylation unclear","Single-lab finding"]},{"year":2020,"claim":"Added ULK1 as a checkpoint kinase phosphorylating RIPK1 (including Ser357) to limit necrosome assembly.","evidence":"In vitro kinase assay with MS site mapping; siRNA knockdown; phosphomimetic mutants","pmids":["32320653"],"confidence":"Medium","gaps":["In vivo relevance not established","Functional hierarchy relative to other inhibitory phosphosites unknown"]},{"year":2021,"claim":"Identified the PPP1R3G/PP1γ phosphatase as the activating switch that removes inhibitory phosphorylation (e.g. Ser25) at complex I to license RIPK1 death signaling, balancing the inhibitory kinases.","evidence":"Genome-wide CRISPR screen, PP1γ-binding mutant rescue, RIPK1-S25A, Ppp1r3g-/- mice in TNF-SIRS","pmids":["34862394"],"confidence":"High","gaps":["Full set of dephosphorylated sites not enumerated","How phosphatase recruitment is timed during signaling unclear"]},{"year":2021,"claim":"Expanded RIPK1 platforms to the lysosomal Rag-Ragulator supercomplex, which licenses RIPK1-dependent caspase-8 activation and pyroptosis during Yersinia infection independent of mTORC1, and showed RIPK1 loss drives RIPK3/caspase-8-mediated T cell senescence.","evidence":"Genome-wide CRISPR screen; Rag-Ragulator/RIPK1/caspase-8 Co-IP and GTPase mutants; T cell conditional KO with double rescue","pmids":["35058659","36696505"],"confidence":"High","gaps":["How Rag-Ragulator tethering activates RIPK1 mechanistically unclear","Generality beyond Yersinia infection not established"]},{"year":2022,"claim":"Uncovered tyrosine phosphorylation (JAK1/SRC at Y384) as an inhibitory checkpoint coupling RIPK1 restraint to MK2 recruitment, and a nuclear chromatin function whereby RIPK1 phosphorylates the BAF subunit SMARCC2 to drive proinflammatory transcription.","evidence":"JAK1/SRC kinase assays and Ripk1-Y383F knock-in mice; nuclear RIPK1–BAF Co-IP, ChIP-seq, SMARCC2 phosphorylation","pmids":["36329033","35661830"],"confidence":"Medium","gaps":["Nuclear translocation trigger for RIPK1 not defined","BAF/SMARCC2 finding from single lab without genetic in vivo confirmation"]},{"year":2022,"claim":"Extended RIPK1 scaffold function to immune evasion and IFN tonic control, with RIPK1 ubiquitin scaffolding shaping an immunosuppressive chemokine program and a caspase-8-restrained RIPK1–TBK1 axis tuning type I IFN.","evidence":"Domain-specific RIPK1 rescue in cancer cells with TIL analysis; RIPK1–TBK1 Co-IP and caspase-8/RIPK1 double-KO IFN assays","pmids":["35417675","36198273"],"confidence":"Medium","gaps":["Direct chemokine targets of scaffold RIPK1 not mapped","Single-lab observations"]},{"year":2023,"claim":"Established metabolic and oxygen-sensing checkpoints on RIPK1 via AMPK phosphorylation at Ser415, EGLN1 prolyl hydroxylation/pVHL binding, and SENP1-mediated deSUMOylation, connecting RIPK1 activation thresholds to energy and hypoxia states.","evidence":"AMPK kinase assay and RIPK1-S415A mice; prolyl hydroxylation/pVHL Co-IP with Vhl-KO; SENP1-KO mice with SUMOylation and kinase-dead rescue","pmids":["37384704","37400498","36414671"],"confidence":"Medium","gaps":["Integration of these modifications at a single signaling complex unclear","Most rely on single conditional-KO systems"]},{"year":2024,"claim":"Resolved the structural and additional gating logic of RIPK1: the RHIM forms an N-shaped amyloid via the IQIG tetrad that templates RIPK1/RIPK3 heterotypic fibrils, and the death domain independently gates ZBP1/TRIF-driven RIPK3 activation through oligomerization and FADD interaction.","evidence":"Solid-state NMR of the RHIM domain and RIPK1/RIPK3 mixing; Ripk1-R588E knock-in mice with multiple genetic rescues and biochemical RIPK3 activation assays","pmids":["39143113","38744293"],"confidence":"High","gaps":["Full-length complex architecture not determined","How DD oligomerization is regulated upstream unclear"]},{"year":2024,"claim":"Defined a broad metabolic/PTM regulatory network controlling RIPK1 kinase licensing—DHHC5 palmitoylation, PARP5A/RNF146 PARdU-driven degradation, UDP-glucuronate binding, O-GlcNAcylation, and spermidine acetylhypusination—linking nutrient and metabolite status to cell death and disease (NASH, RCC, diabetic vasculopathy).","evidence":"Acyl-RAC palmitoylation and DHHC5 KO; phase separation/PARylation/K376 ubiquitination assays; UDP-glucuronate binding with UGDH KO; OGT Co-IP and site mapping; acetylhypusination identification with NAT1-KO mice","pmids":["39471814","38272024","37169760","39276723","39511379"],"confidence":"Medium","gaps":["Hierarchy and cross-talk among these PTMs not integrated","Most are single-lab biochemical characterizations"]},{"year":2024,"claim":"Linked RIPK1 to nuclear-envelope necroptosis and inflammatory feed-forward circuits, with prelamin A recruiting RIPK1 to drive nuclear MLKL activation and a RIPK1/JAK1/RIPK3–STAT1 complex sustaining alloreactive T cell responses in GVHD.","evidence":"Prelamin A–RIPK1 nuclear Co-IP with RIPK3/MLKL rescue in Zmpste24-/- mice; RIPK1/RIPK3–JAK1 Co-IP and STAT1 assays with IEC conditional KO in HSCT model","pmids":["38538837","36356302"],"confidence":"Medium","gaps":["Generality of nuclear-envelope necroptosis beyond progeroid context unclear","Direct vs assembled-complex contribution of RIPK1 to STAT1 activation not separated"]},{"year":null,"claim":"How the many parallel inhibitory and activating modifications are integrated in space and time on a single RIPK1 molecule to set the survival/inflammation/death threshold remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model ordering the PTM checkpoints","Structure of full-length RIPK1 in complex I/II not determined","Triggers for nuclear vs cytosolic RIPK1 functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[15,26]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[9,11,15,26]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,7,21]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[15,20]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[15,28]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[28]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[17]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,2,7,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,20,27,35]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,14,25]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[9,13,24]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[15]}],"complexes":["TNFR1 signaling complex (complex I)","complex II / necrosome","BAF chromatin-remodeling complex","Rag-Ragulator supercomplex"],"partners":["RIPK3","FADD","CASP8","TBK1","TRAF2","ZBP1","JAK1","OTUD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13546","full_name":"Receptor-interacting serine/threonine-protein kinase 1","aliases":["Cell death protein RIP","Receptor-interacting protein 1","RIP-1"],"length_aa":671,"mass_kda":75.9,"function":"Serine-threonine kinase which is a key regulator of TNF-mediated apoptosis, necroptosis and inflammatory pathways (PubMed:17703191, PubMed:24144979, PubMed:31827280, PubMed:31827281, PubMed:32657447, PubMed:35831301). Exhibits kinase activity-dependent functions that regulate cell death and kinase-independent scaffold functions regulating inflammatory signaling and cell survival (PubMed:11101870, PubMed:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283). Has kinase-independent scaffold functions: upon binding of TNF to TNFR1, RIPK1 is recruited to the TNF-R1 signaling complex (TNF-RSC also known as complex I) where it acts as a scaffold protein promoting cell survival, in part, by activating the canonical NF-kappa-B pathway (By similarity). Kinase activity is essential to regulate necroptosis and apoptosis, two parallel forms of cell death: upon activation of its protein kinase activity, regulates assembly of two death-inducing complexes, namely complex IIa (RIPK1-FADD-CASP8), which drives apoptosis, and the complex IIb (RIPK1-RIPK3-MLKL), which drives necroptosis (By similarity). RIPK1 is required to limit CASP8-dependent TNFR1-induced apoptosis (By similarity). In normal conditions, RIPK1 acts as an inhibitor of RIPK3-dependent necroptosis, a process mediated by RIPK3 component of complex IIb, which catalyzes phosphorylation of MLKL upon induction by ZBP1 (PubMed:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283). Inhibits RIPK3-mediated necroptosis via FADD-mediated recruitment of CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis (PubMed:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283). Required to inhibit apoptosis and necroptosis during embryonic development: acts by preventing the interaction of TRADD with FADD thereby limiting aberrant activation of CASP8 (By similarity). In addition to apoptosis and necroptosis, also involved in inflammatory response by promoting transcriptional production of pro-inflammatory cytokines, such as interleukin-6 (IL6) (PubMed:31827280, PubMed:31827281). Phosphorylates RIPK3: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (PubMed:19524513). Phosphorylates DAB2IP at 'Ser-728' in a TNF-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade (PubMed:15310755, PubMed:17389591). Required for ZBP1-induced NF-kappa-B activation in response to DNA damage (By similarity)","subcellular_location":"Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q13546/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RIPK1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RIPK1","total_profiled":1310},"omim":[{"mim_id":"620886","title":"tRNA METHYLTRANSFERASE 6, NONCATALYTIC SUBUNIT; TRMT6","url":"https://www.omim.org/entry/620886"},{"mim_id":"620885","title":"tRNA METHYLTRANSFERASE 61A; TRMT61A","url":"https://www.omim.org/entry/620885"},{"mim_id":"620880","title":"AUTOINFLAMMATION WITH ARTHRITIS AND VASCULITIS; AIARV","url":"https://www.omim.org/entry/620880"},{"mim_id":"620795","title":"AUTOINFLAMMATION WITH EPISODIC FEVER AND IMMUNE DYSREGULATION; AIFID","url":"https://www.omim.org/entry/620795"},{"mim_id":"620293","title":"TMEM9 DOMAIN FAMILY, MEMBER B; TMEM9B","url":"https://www.omim.org/entry/620293"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RIPK1"},"hgnc":{"alias_symbol":["RIP","RIP1","RIP-1"],"prev_symbol":[]},"alphafold":{"accession":"Q13546","domains":[{"cath_id":"1.10.510.10","chopping":"13-304","consensus_level":"medium","plddt":88.4654,"start":13,"end":304},{"cath_id":"1.10.533.10","chopping":"570-669","consensus_level":"high","plddt":85.9299,"start":570,"end":669}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13546","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13546-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13546-F1-predicted_aligned_error_v6.png","plddt_mean":69.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RIPK1","jax_strain_url":"https://www.jax.org/strain/search?query=RIPK1"},"sequence":{"accession":"Q13546","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13546.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13546/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13546"}},"corpus_meta":[{"pmid":"30467385","id":"PMC_30467385","title":"Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases.","date":"2019","source":"Nature reviews. 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Knock-in mice expressing RIPK1(D325A), which cannot be cleaved by caspase-8, die mid-gestation from TNF- and RIPK1-kinase-activity-dependent cell death involving FADD-caspase-8. Lethality was prevented by loss of TNFR1 or combined loss of MLKL and FADD, but not by loss of MLKL alone, demonstrating that cleavage of RIPK1 by caspase-8 dismantles death-inducing complexes.\",\n      \"method\": \"Knock-in mouse models (RIPK1-D325A, caspase-8 catalytic mutants, MLKL-KO, FADD-KO, TNFR1-KO); embryo histology; genetic epistasis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal knock-in and knockout mouse models with clear genetic epistasis; replicated across two independent Nature papers (PMID 31511692, 31827281)\",\n      \"pmids\": [\"31511692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Heterozygous missense mutations D324N, D324H, and D324Y in human RIPK1 prevent caspase-8 cleavage, sensitizing cells to RIPK1-kinase-dependent apoptosis and necroptosis induced by TNF and causing an early-onset autoinflammatory periodic fever syndrome. Mouse knock-in Ripk1(D325A/D325A) embryonic lethality was rescued by combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone; loss of RIPK1 kinase activity also prevented lethality.\",\n      \"method\": \"Human genetic sequencing; knock-in mouse models (Ripk1D325A); cell death assays in patient-derived PBMCs and fibroblasts; genetic epistasis with Ripk3, Mlkl, Casp8 deletions\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — two independent papers (PMID 31827281, 31827280) with human genetics plus complementary mouse knock-in models and multiple orthogonal rescue experiments\",\n      \"pmids\": [\"31827281\", \"31827280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The RHIM domain of RIPK1 suppresses ZBP1-mediated activation of RIPK3-MLKL necroptosis. Mice with RHIM-mutant RIPK1 (IQIG→AAAA) died perinatally due to RIPK3/MLKL-dependent necroptosis; this lethality was prevented by ZBP1 deficiency, RIPK3 deficiency, or MLKL deficiency. ZBP1 interacted strongly with phospho-RIPK3 in RHIM-mutant cells but not in wild-type cells, demonstrating that the RIPK1 RHIM functions as a brake preventing ZBP1 from engaging RIPK3.\",\n      \"method\": \"Knock-in mouse models (RIPK1-RHIM mutant); genetic rescue with ZBP1-KO, RIPK3-KO, MLKL-KO; Co-immunoprecipitation of ZBP1–RIPK3 complex\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — two simultaneous independent Nature papers (PMID 27819681, 27819682) with knock-in mice, multiple genetic rescues, and Co-IP validation\",\n      \"pmids\": [\"27819681\", \"27819682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Optineurin (OPTN) actively suppresses RIPK1-dependent signaling by regulating RIPK1 turnover. Loss of OPTN in the CNS leads to progressive dysmyelination and axonal degeneration via engagement of RIPK1, RIPK3, and MLKL necroptotic machinery.\",\n      \"method\": \"OPTN-knockout mice; pharmacological RIPK1 inhibition; histopathology of human ALS samples; genetic rescue with RIPK1/RIPK3 deficiency\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mouse model plus pharmacological inhibition with defined cellular phenotype, corroborated in human ALS tissue\",\n      \"pmids\": [\"27493188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TBK1 and IKKε phosphorylate RIPK1 within the TNFR1 signaling complex (TNFR1-SC) to prevent RIPK1-dependent cell death. LUBAC-generated linear (M1) ubiquitin enables recruitment and activation of TBK1 and IKKε at the TNFR1-SC via NEMO-TANK-NAP1 adaptors; this checkpoint is essential in vivo to prevent TNF-induced lethal shock.\",\n      \"method\": \"Biochemical reconstitution of TNFR1-SC; RIPK1 phosphorylation assays; TBK1/IKKε kinase-dead mutants; in vivo TNF shock model\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic phosphorylation assays, signaling complex reconstitution, and in vivo epistasis in a single rigorous study (PMID 30420664), independently supported by PMID 30146158\",\n      \"pmids\": [\"30420664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TBK1 is an endogenous inhibitor of RIPK1: embryonic lethality of Tbk1-/- mice depends on RIPK1 kinase activity, placing TBK1 upstream of RIPK1 as a negative regulator. Reduced TAK1 expression in aging brains cooperates with TBK1 haploinsufficiency to promote RIPK1-driven ALS/FTD hallmarks.\",\n      \"method\": \"Tbk1-/- mice rescued by RIPK1 kinase inhibition; Tbk1+/- aged mice with genetic/pharmacological RIPK1 inhibition; epistasis with TAK1 expression\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models plus pharmacological inhibition with defined phenotypic rescue in a single comprehensive study\",\n      \"pmids\": [\"30146158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RIPK1 both promotes and suppresses RIPK3 oligomerization. Chemically enforced oligomerization of RIPK3 is sufficient to induce necroptosis independent of RIPK1 activity; however, RIPK1 intrinsically suppresses spontaneous RIPK3 activation in the cytosol, as cells lacking RIPK1 show increased spontaneous RIPK3-dependent death, while catalytically inactive or inhibited RIPK1 protects against this death.\",\n      \"method\": \"Inducible dimerization/oligomerization RIPK3 constructs; RIPK1-KO and kinase-dead cells; necroptosis assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic and pharmacological tools, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"24902904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ubiquitination of RIPK1 at K376 is required to suppress RIPK1 kinase activity during embryogenesis. Mice expressing RIPK1(K376R) die during embryogenesis; lethality is fully rescued by combined deletion of Fadd and Ripk3 or Mlkl, and by RIPK1 kinase inhibitor treatment. K376R mutation promotes complex II formation and increases RIPK1 activation downstream of TNFR1.\",\n      \"method\": \"Knock-in mouse model (RIPK1-K376R); pharmacological RIPK1 kinase inhibitor; genetic rescue with Fadd/Ripk3/Mlkl/Tnfr1 deletion; immunoprecipitation of complex II\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — knock-in mouse with multiple genetic rescues and mechanistic complex II pulldown, two independent papers (PMID 31519886, 32999468) converging on same site\",\n      \"pmids\": [\"31519886\", \"32999468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OTUD1 deubiquitinase physically interacts with RIPK1 and selectively cleaves K63-linked polyubiquitin chains from RIPK1, thereby inhibiting recruitment of NEMO and suppressing NF-κB activation. Loss of OTUD1 promotes colonic inflammation via excessive RIPK1-mediated NF-κB signaling.\",\n      \"method\": \"Co-immunoprecipitation of OTUD1–RIPK1; ubiquitin linkage-specific deubiquitination assays; OTUD1-KO mice; bone marrow transplantation\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, biochemical ubiquitin assay, and in vivo mouse model in single lab\",\n      \"pmids\": [\"34876703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AMPK phosphorylates RIPK1 at Ser415 to suppress energy-stress-induced RIPK1 activation and cell death. Inhibiting pS415-RIPK1 (via AMPK deficiency or RIPK1-S415A mutation) promotes RIPK1 activation. Genetic inactivation of RIPK1 protects against ischemic injury in myeloid Ampkα1-deficient mice, establishing AMPK as an upstream suppressor of RIPK1 in the metabolic checkpoint.\",\n      \"method\": \"In vitro kinase assays (AMPK phosphorylates RIPK1); knock-in RIPK1-S415A mice; Ampkα1-myeloid KO mice; ischemia model with genetic rescue\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro kinase assay plus knock-in mouse and in vivo ischemia model; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"37384704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ULK1 phosphorylates RIPK1 at multiple sites including Ser357 in the intermediate domain. ULK1-mediated phosphorylation reduces complex IIb/necrosome assembly and TNF-induced cell death; ULK1 depletion enhances TNF-induced cell death.\",\n      \"method\": \"In vitro kinase assay; mass spectrometry identification of ULK1 phosphorylation sites on RIPK1; siRNA knockdown; TNF-induced cell death assays; phosphomimetic mutants\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro kinase assay with site identification, single lab\",\n      \"pmids\": [\"32320653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAK1 and SRC (non-receptor tyrosine kinases) phosphorylate RIPK1 at Y384 (Y383 in mouse), suppressing TNF-induced cell death. Ripk1(Y383F/Y383F) knock-in mice develop systemic inflammation and emergency haematopoiesis; mechanistically, the Y383F mutation promotes RIPK1 kinase activation and impairs MK2 recruitment/activation. Inflammation is prevented by RIPK1 kinase inhibition or deletion of TNFR1 or RIPK3+Caspase8.\",\n      \"method\": \"In vitro kinase assay (JAK1/SRC phosphorylate RIPK1-Y384); knock-in mouse model (Ripk1-Y383F); genetic rescue; cell death assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct kinase assay plus knock-in mouse with multiple genetic rescues demonstrating in vivo relevance\",\n      \"pmids\": [\"36329033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SENP1 (SUMO-specific protease) deSUMOylates RIPK1 within the TNF-RSC, keeping RIPK1 in check. Loss of SENP1 leads to SUMOylation of RIPK1, which re-orchestrates the TNF-RSC and modulates ubiquitination patterns and kinase activity of RIPK1, sensitizing cells to RIPK1-kinase-dependent apoptosis.\",\n      \"method\": \"Hepatocyte-specific SENP1-KO mice; RIPK1 SUMOylation assays; TNF-RSC immunoprecipitation; rescue by RIPK1 kinase-dead knockin\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical SUMOylation assay and Co-IP plus conditional KO mouse with RIPK1 kinase-dead rescue, single lab\",\n      \"pmids\": [\"36414671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EGLN1-mediated prolyl hydroxylation of RIPK1 promotes its binding to pVHL, suppressing RIPK1 kinase activation under normoxic conditions. Prolonged hypoxia reduces prolyl hydroxylation of RIPK1, thereby promoting RIPK1 kinase activation and downstream cell death and inflammation independent of TNFα-TNFR1.\",\n      \"method\": \"Prolyl hydroxylation assays; pVHL co-immunoprecipitation; hepatocyte-specific Vhl-KO mice; EGLN1 inhibitor experiments; cell death assays under hypoxia\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical hydroxylation/binding assays plus conditional mouse KO, single lab\",\n      \"pmids\": [\"37400498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PPP1R3G recruits protein phosphatase 1 gamma (PP1γ) to complex I to dephosphorylate inhibitory phosphorylation sites on RIPK1 (including Ser25), enabling RIPK1 kinase activation and cell death. PPP1R3G mutants unable to bind PP1γ fail to rescue RIPK1 activation; Ppp1r3g-/- mice are protected from TNF-induced SIRS.\",\n      \"method\": \"CRISPR whole-genome KO screen; Co-IP of PPP1R3G–PP1γ–RIPK1; PPP1R3G binding-mutant rescue; RIPK1-S25A mutation; Ppp1r3g-/- mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genome-wide screen plus biochemical validation with Co-IP, mutagenesis, in vivo mouse model; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"34862394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Activated nuclear RIPK1 physically associates with the BAF chromatin-remodeling complex. Upon RIPK1 activation, the RIPK1/BAF complex is recruited to active enhancers and promoters (marked by H3K4me1 and H3K27ac), where RIPK1 phosphorylates SMARCC2, a key BAF subunit, promoting chromatin remodeling and transcription of specific proinflammatory genes independent of cell death.\",\n      \"method\": \"Co-immunoprecipitation of nuclear RIPK1 with BAF; ChIP-seq for RIPK1 on H3K4me1/H3K27ac loci; phosphorylation assay for SMARCC2; nuclear fractionation; RIPK1 kinase inhibitor\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP-seq, and phosphorylation assay in single lab, novel nuclear function\",\n      \"pmids\": [\"35661830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RIPK1 promotes mTORC1 inhibition during energetic stress by mediating the interaction between AMPK and TSC2 and facilitating TSC2 phosphorylation at Ser1387. RIPK1 loss results in high basal mTORC1 activity, defective lysosomes, and accumulation of RIPK3 and caspase-8, sensitizing cells to death under low glucose or metformin.\",\n      \"method\": \"Co-immunoprecipitation of RIPK1–AMPK–TSC2; TSC2 phosphorylation assays; mTORC1 activity measurement in RIPK1-deficient cells/mice; lysosome functional assays; genetic rescue by mTORC1 inhibition\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, biochemical phosphorylation, and cell/mouse phenotype, single lab\",\n      \"pmids\": [\"33271062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The lysosomal Rag-Ragulator supercomplex licenses RIPK1-dependent caspase-8 activation and pyroptosis during Yersinia infection. FADD, RIPK1, and caspase-8 are recruited to Rag-Ragulator, causing RIPK1 phosphorylation and caspase-8 activation. This depends on Rag GTPase activity and lysosomal tethering but not mTORC1.\",\n      \"method\": \"Genome-wide CRISPR screen; Co-immunoprecipitation of FADD/RIPK1/caspase-8 with Rag-Ragulator; Rag GTPase mutants; lysosomal tethering mutants; caspase-8 activity assays\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — unbiased genome-wide CRISPR screen with mechanistic Co-IP and mutant validation, rigorous controls distinguishing from mTORC1\",\n      \"pmids\": [\"35058659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss of RIPK1 in liver parenchymal cells (LPC) leads to TNF-dependent proteasomal degradation of TRAF2 in a kinase-independent manner, thereby activating caspase-8. Combined loss of RIPK1 and TRAF2 in LPC impairs NF-κB activation and promotes spontaneous hepatocellular carcinoma, establishing a RIPK1–TRAF2 tumor-suppressive axis.\",\n      \"method\": \"LPC-specific Ripk1/Traf2 conditional KO mice; TRAF2 ubiquitination/degradation assays; caspase-8 activity; TNF treatment; spontaneous tumor monitoring\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse models with biochemical validation of TRAF2 degradation and caspase-8 activation, single lab\",\n      \"pmids\": [\"28017612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Kinase-independent functions of RIPK1 promote hepatocyte survival via cooperation with NF-κB/RelA signaling. Combined RIPK1 and RelA deficiency in liver parenchymal cells causes hepatocyte apoptosis and spontaneous chronic liver disease/cancer independent of TNFR1. RIPK1 kinase inactivity does not inhibit DEN-induced liver tumor formation, showing kinase-independent pro-tumorigenic RIPK1 scaffold function.\",\n      \"method\": \"LPC-specific Ripk1/RelA double conditional KO; kinase-dead RIPK1 knock-in mice; DEN-induced liver tumor models; genetic rescue with TNFR1 deletion\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple conditional KO mouse models with defined phenotype, single lab\",\n      \"pmids\": [\"28628031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RIPK1 and RIPK3 kinase activities promote pro-inflammatory gene expression (sustained ERK, c-Fos, NF-κB activation) downstream of TLR4/LPS in macrophages, independent of their cell death functions. This regulation requires the adaptor TRIF and proceeds cell-autonomously; it accounts for acute LPS-induced inflammatory responses in vivo.\",\n      \"method\": \"Primary macrophage KO/kinase-inhibitor experiments; LPS stimulation with caspase-8 inhibition; in vivo LPS challenge with genetic/pharmacological RIPK1/RIPK3 inhibition; signaling pathway analysis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and pharmacological tools with in vivo validation, single lab\",\n      \"pmids\": [\"27396959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The RIPK1 death domain (DD) prevents ZBP1- and TRIF-mediated activation of RIPK3. A mutation disrupting the RIPK1 DD (R588E) caused perinatal lethality from ZBP1-mediated necroptosis, and postnatal inflammatory pathology via TNFR1/TRADD/TRIF-dependent RIPK3 signaling. Biochemically, ZBP1- and TRIF-mediated RIPK3 activation required RIPK1 kinase activity in wild-type cells but not in Ripk1(R588E) cells, indicating that DD-dependent RIPK1 oligomerization and FADD interaction gate the mechanism of RIPK3 activation.\",\n      \"method\": \"Knock-in mouse model (Ripk1-R588E); genetic rescue with ZBP1-KO, RIPK3-KO, MLKL-KO, TNFR1-KO, TRADD-KO; biochemical RIPK3 activation assays comparing WT vs R588E cells\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — knock-in mouse with multiple orthogonal genetic rescues and mechanistic biochemical assays distinguishing kinase-dependent vs DD-dependent pathways\",\n      \"pmids\": [\"38744293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"S-palmitoylation is a licensing post-translational modification for RIPK1 kinase. TNF induces DHHC5-mediated palmitoylation of RIPK1, which depends on K63-linked ubiquitination of RIPK1, promotes homo-interaction of the RIPK1 kinase domain, and enhances RIPK1 kinase activity and cell death when cell death checkpoints are disabled.\",\n      \"method\": \"Palmitoylation assays (acyl-RAC); DHHC5 KO and overexpression; K63-ubiquitination requirement tested by mutation; RIPK1 kinase domain interaction assays; cell death assays in murine NASH model\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct palmitoylation biochemical assays with mechanistic domain interaction studies and in vivo disease model, single lab\",\n      \"pmids\": [\"39471814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PARP5A and RNF146 form liquid-like condensates via phase separation (recruited by TAX1BP1) to perform poly-ADP-ribosylation (PARylation) and PARylation-dependent ubiquitination (PARdU) of activated RIPK1. PARdU occurs predominantly at K376 of mouse RIPK1 and promotes proteasomal degradation of kinase-activated RIPK1, restraining necroptosis.\",\n      \"method\": \"Phase separation assays; PARylation assays; Co-IP of PARP5A/RNF146 with RIPK1; ubiquitination assays at K376; proteasome inhibitor experiments; necroptosis readouts in mouse embryonic fibroblasts\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct biochemical assays for PARylation and ubiquitination plus phase separation characterization, single lab\",\n      \"pmids\": [\"38272024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UDP-glucuronate, produced by UGDH from UDP-glucose, directly binds to the kinase domain of RIPK1 and inhibits its activation. UGDH deficiency in hepatocytes promotes RIPK1-kinase-dependent apoptosis and NASH progression; recovering UDP-glucuronate levels suppresses liver damage even after disease onset.\",\n      \"method\": \"Direct binding assay (UDP-glucuronate to RIPK1 kinase domain); UGDH conditional KO mice; rescue by RIPK1 kinase-dead knockin; metabolomic measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding assay plus KO mouse with genetic rescue, single lab\",\n      \"pmids\": [\"37169760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PPP1R3G/PP1γ phosphatase promotes RIPK1-dependent apoptosis and necroptosis by dephosphorylating inhibitory phosphorylations of RIPK1 (including Ser25) within complex I. A PPP1R3G mutant that cannot bind PP1γ fails to rescue RIPK1 activation; Ppp1r3g-/- mice are protected from TNF-induced SIRS.\",\n      \"method\": \"CRISPR genome-wide KO screen; Co-IP; PP1γ-binding mutant; RIPK1 S25A mutation; Ppp1r3g-/- mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — unbiased screen, mechanistic Co-IP with mutagenesis, and in vivo validation\",\n      \"pmids\": [\"34862394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The PP6 phosphatase holoenzyme (PPP6C catalytic subunit + PPP6R1/R2/R3 regulatory subunits) promotes RIPK1-dependent PANoptosis by enhancing pro-death autophosphorylation of RIPK1 at Ser166 and reducing pro-survival phosphorylation at Ser321. PP6 regulatory subunits act redundantly.\",\n      \"method\": \"CRISPR cell death screen; genetic knockdown/KO of PP6 components; Western blot for RIPK1 pS166/pS321; TAK1 inhibitor-induced PANoptosis assay\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen with biochemical phosphorylation validation, single lab\",\n      \"pmids\": [\"38807188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"When caspase-8 is deleted or inhibited, RIPK1 interacts with TBK1 to drive elevated type I IFN production. Combined deletion of caspase-8 and RIPK1 reduces type I IFN signaling, demonstrating that caspase-8 negatively regulates tonic IFN production by inhibiting the RIPK1-TBK1 axis.\",\n      \"method\": \"Caspase-8 KO/inhibitor experiments; Co-IP of RIPK1–TBK1; IFN production assays; combined caspase-8/RIPK1 double-KO mice\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and double-KO epistasis with IFN measurements, single lab\",\n      \"pmids\": [\"36198273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In ZMPSTE24-deficient cells, accumulated farnesylated prelamin A recruits RIPK1 to the nucleus upon TNF stimulation, where kinase-activated RIPK1 promotes RIPK3-mediated MLKL activation at the nuclear envelope, leading to nuclear envelope disruption and necroptosis. Genetic inactivation of necroptosis ameliorates progeroid phenotypes in Zmpste24-/- mice.\",\n      \"method\": \"Nuclear fractionation and Co-IP of prelamin A–RIPK1; farnesylation inhibitor rescue; RIPK3/MLKL KO rescue in Zmpste24-/- mice; live-cell imaging of nuclear MLKL activation\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical nuclear Co-IP, farnesylation dependence, genetic rescue in KO mice, single lab\",\n      \"pmids\": [\"38538837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Amyloid structure of mouse RIPK1 RHIM-containing domain (82-residue sequence) was determined by solid-state NMR, revealing an 'N'-shaped fibril subunit with four β-strands. The central β-strand is formed by the conserved IQIG tetrad. Upon mixing with RIPK3, RIPK1/RIPK3 complex fibrils form with altered structural rigidity, consistent with RHIM-mediated heterotypic amyloid interaction.\",\n      \"method\": \"Solid-state NMR; structural determination of RIPK1 RHIM amyloid; mixing experiments with RIPK3 to form heterotypic fibrils\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — solid-state NMR structural determination with functional domain mapping; single lab but rigorous structural method\",\n      \"pmids\": [\"39143113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SMYD2 histone methyltransferase targets RIPK1 (non-histone substrate) and inhibits RIPK1 phosphorylation, thereby suppressing TNF-induced apoptosis and necroptosis in colon tumor cells. SMYD2 deficiency sensitizes tumor cells to TNF-induced cell death and impairs tumor growth in two independent murine cancer models.\",\n      \"method\": \"Co-IP of SMYD2–RIPK1; RIPK1 phosphorylation assays in SMYD2-deficient cells; SMYD2 pharmacological inhibition; in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and phosphorylation assays with in vivo tumor model validation, single lab\",\n      \"pmids\": [\"35022391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In cancer cells, RIPK1 diverts TNF signaling through NF-κB and away from cell death via its ubiquitin scaffolding (non-kinase) function, promoting an immunosuppressive chemokine program that decreases T and NK cell infiltration. This RIPK1-mediated resistance to immune checkpoint blockade requires the scaffold but not kinase function.\",\n      \"method\": \"Genetic interaction screen in cancer cells; RIPK1 KO and reconstitution with scaffold vs kinase mutants; NF-κB and cell death assays; in vivo tumor-infiltrating lymphocyte analysis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic screen with domain-specific rescue experiments and in vivo validation, single lab\",\n      \"pmids\": [\"35417675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"O-GlcNAcylation of RIPK1 at Ser331, Ser440, and Ser669 by OGT (which interacts with RIPK1 via its TPR domain) regulates RIPK1 ubiquitination and the formation of the RIPK1/FADD/Caspase-8 complex, thereby inhibiting sunitinib-induced RIPK1-dependent apoptosis in renal cell carcinoma.\",\n      \"method\": \"Co-IP of OGT–RIPK1; mass spectrometry identification of O-GlcNAcylation sites; site-specific mutation of Ser331/440/669; RIPK1/FADD/Caspase-8 complex pulldown; cell death assays\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry site identification, Co-IP, and mutagenesis with functional assay, single lab\",\n      \"pmids\": [\"39276723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Spermidine mediates acetylhypusination (a novel PTM combining acetylation with hypusine-like modification) of RIPK1, suppressing RIPK1 kinase-mediated cell death. NAT1 (murine) / NAT2 (human) deficiency reduces cellular spermidine levels, leading to loss of this suppressive modification on RIPK1 and promoting diabetic vascular pathology reversible by RIPK1 inhibition.\",\n      \"method\": \"Identification of acetylhypusination modification on RIPK1; spermidine supplementation rescue; NAT1-KO mice; RIPK1 inhibitor in vivo; human diabetic vascular tissue analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — novel PTM biochemically identified with in vivo rescue and patient tissue validation, single lab\",\n      \"pmids\": [\"39511379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RIPK1 deficiency in T cells causes premature senescence mediated by RIPK3 and caspase-8. Combined deficiency of RIPK3 and caspase-8 inhibition restores proliferative responses and reduces mTORC1 hyperactivation and senescence-related gene expression in RIPK1-deficient CD4 T cells, demonstrating that RIPK1 normally blocks RIPK3/caspase-8-mediated T cell senescence.\",\n      \"method\": \"T cell-specific RIPK1 conditional KO mice; combined RIPK3-KO and caspase-8 inhibition; mTORC1 activity measurement; senescence marker assays; proliferation assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mice with genetic double-rescue experiments; single lab\",\n      \"pmids\": [\"36696505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RIPK1 forms a complex with JAK1 and RIPK3 to promote STAT1 activation in intestinal epithelial cells, driving MHC class II and chemokine expression that sustains alloreactive T cell responses in GVHD. Interferon-γ from alloreactive T cells amplifies this via JAK/STAT1-dependent enhancement of RIPK1/RIPK3 signaling, creating a feed-forward inflammatory cascade.\",\n      \"method\": \"Co-IP of RIPK1/RIPK3 with JAK1; STAT1 activation assays; IEC-specific RIPK3 conditional KO; JAK/STAT1 pathway analysis; allogeneic HSCT mouse model; selective RIPK1 inhibitor (Zharp1-211)\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, conditional KO, and pharmacological inhibition with in vivo GVHD model, single lab\",\n      \"pmids\": [\"36356302\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RIPK1 is a multifunctional serine/threonine kinase that acts as a signaling node downstream of death receptors (primarily TNFR1), TLRs, and ZBP1: in its scaffold (kinase-inactive) form it promotes cell survival and NF-κB/MAPK inflammatory signaling, whereas kinase activation drives apoptosis, necroptosis, and transcriptional inflammation via chromatin remodeling; its activity is tightly controlled by multiple post-translational modifications—K63/linear ubiquitination at K376 (by cIAPs/LUBAC), inhibitory phosphorylation at Ser25 (by IKKα/β), Ser321 (by MK2), Ser415 (by AMPK), and Y384 (by JAK1/SRC), activating autophosphorylation at Ser166, prolyl hydroxylation (by EGLN1/pVHL), SUMOylation, palmitoylation, acetylhypusination, and O-GlcNAcylation—as well as caspase-8 cleavage at Asp325 that dismantles death complexes; the RHIM domain sequesters ZBP1 from activating RIPK3, and nuclear RIPK1 directly phosphorylates the BAF complex subunit SMARCC2 to drive proinflammatory gene transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RIPK1 is a master signaling node downstream of TNFR1 and other innate immune receptors that integrates ubiquitin and phosphorylation signals to switch cells between survival, inflammation, and regulated death, with its kinase activity gating apoptosis and necroptosis while its scaffold function supports survival and NF-\\u03baB signaling [#7, #25, #31]. A dense layer of post-translational modifications keeps RIPK1 kinase activity restrained as a default state: K63-linked ubiquitination at K376 suppresses complex II formation [#7]; inhibitory phosphorylations placed by TBK1/IKK\\u03b5 within the TNFR1 signaling complex [#4, #5], by AMPK at Ser415 during energy stress [#9], by ULK1 [#10], and by JAK1/SRC at Y384 [#11] each act as independent checkpoints, while removal of inhibitory phosphorylation by the PPP1R3G/PP1\\u03b3 phosphatase at complex I (e.g. Ser25) and the PP6 holoenzyme (favoring autophosphorylation at Ser166 over Ser321) licenses RIPK1 activation and death [#14, #25, #26]. Additional modifications\\u2014deSUMOylation by SENP1 [#12], EGLN1-mediated prolyl hydroxylation enabling pVHL binding [#13], DHHC5-dependent S-palmitoylation that drives kinase-domain self-association [#22], PARylation-dependent ubiquitination by PARP5A/RNF146 targeting activated RIPK1 for degradation [#23], O-GlcNAcylation by OGT [#32], spermidine-dependent acetylhypusination [#33], and the metabolite UDP-glucuronate binding the kinase domain [#24]\\u2014collectively tune the activation threshold across metabolic and inflammatory contexts. Caspase-8 cleavage at Asp325/Asp324 dismantles death-inducing complexes, and loss of this cleavage causes lethal TNF/kinase-dependent cell death in mice and an autoinflammatory periodic fever syndrome in humans [#0, #1]. Independent of the kinase, the RIPK1 RHIM and death domains restrain ZBP1- and TRIF-driven RIPK3-MLKL necroptosis, the RHIM forming a heterotypic amyloid interface with RIPK3 [#2, #21, #29]. Beyond cell death, RIPK1 drives transcriptional inflammation: activated nuclear RIPK1 associates with the BAF chromatin-remodeling complex and phosphorylates SMARCC2 to remodel enhancers and promoters of proinflammatory genes [#15], and RIPK1/RIPK3 kinase activity sustains pro-inflammatory gene expression downstream of TLR4/TRIF [#20]. RIPK1 also serves kinase-independent metabolic and survival roles, scaffolding AMPK\\u2013TSC2 to restrain mTORC1 [#16] and cooperating with TRAF2 and NF-\\u03baB/RelA to maintain hepatocyte survival, where its loss promotes spontaneous liver cancer [#18, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established that RIPK1 paradoxically both enables and restrains RIPK3-driven necroptosis, framing RIPK1 as a bidirectional regulator rather than a simple activator.\",\n      \"evidence\": \"Inducible RIPK3 oligomerization constructs in RIPK1-KO and kinase-dead cells with necroptosis assays\",\n      \"pmids\": [\"24902904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis for cytosolic suppression of spontaneous RIPK3 activation not resolved\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the RIPK1 RHIM as a brake that prevents ZBP1 from engaging RIPK3, explaining why RHIM-mutant mice die of necroptosis.\",\n      \"evidence\": \"RHIM-mutant knock-in mice with ZBP1/RIPK3/MLKL rescue and ZBP1\\u2013RIPK3 Co-IP\",\n      \"pmids\": [\"27819681\", \"27819682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RHIM-mediated sequestration not defined at this stage\", \"Does not address how the brake is released physiologically\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified upstream regulators of RIPK1 turnover (OPTN) and OTUD1-mediated K63-deubiquitination, and a kinase-independent RIPK1\\u2013TRAF2 tumor-suppressive axis in liver, broadening RIPK1 control beyond its catalytic activity.\",\n      \"evidence\": \"OPTN-KO and conditional Ripk1/Traf2 KO mice; ubiquitin-linkage-specific deubiquitination assays; TRAF2 degradation assays\",\n      \"pmids\": [\"27493188\", \"28017612\", \"27396959\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between ubiquitin editing and complex II assembly incomplete\", \"Tissue-specificity of survival vs death decisions unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed TBK1/IKK\\u03b5 as LUBAC-dependent checkpoint kinases that phosphorylate RIPK1 in the TNFR1-SC, with TBK1 acting genetically upstream of RIPK1 to prevent lethal cell death and neurodegeneration.\",\n      \"evidence\": \"TNFR1-SC reconstitution, kinase-dead TBK1/IKK\\u03b5 mutants, Tbk1-/- mice rescued by RIPK1 kinase inhibition\",\n      \"pmids\": [\"30420664\", \"30146158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise inhibitory phosphosites placed by TBK1/IKK\\u03b5 not fully mapped here\", \"Cooperation with other checkpoint kinases unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed that caspase-8 cleavage of RIPK1 at Asp325/324 dismantles death complexes, and that loss of this cleavage causes TNF/kinase-dependent lethality in mice and a human autoinflammatory disease.\",\n      \"evidence\": \"RIPK1-D325A knock-in mice with genetic epistasis; human sequencing of D324 mutations; patient-derived cell death assays\",\n      \"pmids\": [\"31511692\", \"31827281\", \"31827280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cleavage products redistribute signaling not detailed\", \"Trigger that engages caspase-8 cleavage in homeostasis unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that K376 ubiquitination is required to suppress RIPK1 kinase activity during embryogenesis, linking a specific ubiquitin site to complex II restraint.\",\n      \"evidence\": \"RIPK1-K376R knock-in mice with Fadd/Ripk3/Mlkl rescue and complex II IP\",\n      \"pmids\": [\"31519886\", \"32999468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of ligases/DUBs acting at K376 in vivo not fully assigned here\", \"Ubiquitin linkage type at K376 not resolved in this work\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed kinase-independent metabolic scaffolding by RIPK1, bridging AMPK and TSC2 to restrain mTORC1 and maintain lysosomal homeostasis.\",\n      \"evidence\": \"Co-IP of RIPK1\\u2013AMPK\\u2013TSC2; TSC2 Ser1387 phosphorylation; mTORC1/lysosome assays in RIPK1-deficient cells\",\n      \"pmids\": [\"33271062\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect role of RIPK1 in TSC2 phosphorylation unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Added ULK1 as a checkpoint kinase phosphorylating RIPK1 (including Ser357) to limit necrosome assembly.\",\n      \"evidence\": \"In vitro kinase assay with MS site mapping; siRNA knockdown; phosphomimetic mutants\",\n      \"pmids\": [\"32320653\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance not established\", \"Functional hierarchy relative to other inhibitory phosphosites unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the PPP1R3G/PP1\\u03b3 phosphatase as the activating switch that removes inhibitory phosphorylation (e.g. Ser25) at complex I to license RIPK1 death signaling, balancing the inhibitory kinases.\",\n      \"evidence\": \"Genome-wide CRISPR screen, PP1\\u03b3-binding mutant rescue, RIPK1-S25A, Ppp1r3g-/- mice in TNF-SIRS\",\n      \"pmids\": [\"34862394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of dephosphorylated sites not enumerated\", \"How phosphatase recruitment is timed during signaling unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded RIPK1 platforms to the lysosomal Rag-Ragulator supercomplex, which licenses RIPK1-dependent caspase-8 activation and pyroptosis during Yersinia infection independent of mTORC1, and showed RIPK1 loss drives RIPK3/caspase-8-mediated T cell senescence.\",\n      \"evidence\": \"Genome-wide CRISPR screen; Rag-Ragulator/RIPK1/caspase-8 Co-IP and GTPase mutants; T cell conditional KO with double rescue\",\n      \"pmids\": [\"35058659\", \"36696505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Rag-Ragulator tethering activates RIPK1 mechanistically unclear\", \"Generality beyond Yersinia infection not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered tyrosine phosphorylation (JAK1/SRC at Y384) as an inhibitory checkpoint coupling RIPK1 restraint to MK2 recruitment, and a nuclear chromatin function whereby RIPK1 phosphorylates the BAF subunit SMARCC2 to drive proinflammatory transcription.\",\n      \"evidence\": \"JAK1/SRC kinase assays and Ripk1-Y383F knock-in mice; nuclear RIPK1\\u2013BAF Co-IP, ChIP-seq, SMARCC2 phosphorylation\",\n      \"pmids\": [\"36329033\", \"35661830\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear translocation trigger for RIPK1 not defined\", \"BAF/SMARCC2 finding from single lab without genetic in vivo confirmation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended RIPK1 scaffold function to immune evasion and IFN tonic control, with RIPK1 ubiquitin scaffolding shaping an immunosuppressive chemokine program and a caspase-8-restrained RIPK1\\u2013TBK1 axis tuning type I IFN.\",\n      \"evidence\": \"Domain-specific RIPK1 rescue in cancer cells with TIL analysis; RIPK1\\u2013TBK1 Co-IP and caspase-8/RIPK1 double-KO IFN assays\",\n      \"pmids\": [\"35417675\", \"36198273\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chemokine targets of scaffold RIPK1 not mapped\", \"Single-lab observations\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established metabolic and oxygen-sensing checkpoints on RIPK1 via AMPK phosphorylation at Ser415, EGLN1 prolyl hydroxylation/pVHL binding, and SENP1-mediated deSUMOylation, connecting RIPK1 activation thresholds to energy and hypoxia states.\",\n      \"evidence\": \"AMPK kinase assay and RIPK1-S415A mice; prolyl hydroxylation/pVHL Co-IP with Vhl-KO; SENP1-KO mice with SUMOylation and kinase-dead rescue\",\n      \"pmids\": [\"37384704\", \"37400498\", \"36414671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Integration of these modifications at a single signaling complex unclear\", \"Most rely on single conditional-KO systems\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the structural and additional gating logic of RIPK1: the RHIM forms an N-shaped amyloid via the IQIG tetrad that templates RIPK1/RIPK3 heterotypic fibrils, and the death domain independently gates ZBP1/TRIF-driven RIPK3 activation through oligomerization and FADD interaction.\",\n      \"evidence\": \"Solid-state NMR of the RHIM domain and RIPK1/RIPK3 mixing; Ripk1-R588E knock-in mice with multiple genetic rescues and biochemical RIPK3 activation assays\",\n      \"pmids\": [\"39143113\", \"38744293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length complex architecture not determined\", \"How DD oligomerization is regulated upstream unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a broad metabolic/PTM regulatory network controlling RIPK1 kinase licensing\\u2014DHHC5 palmitoylation, PARP5A/RNF146 PARdU-driven degradation, UDP-glucuronate binding, O-GlcNAcylation, and spermidine acetylhypusination\\u2014linking nutrient and metabolite status to cell death and disease (NASH, RCC, diabetic vasculopathy).\",\n      \"evidence\": \"Acyl-RAC palmitoylation and DHHC5 KO; phase separation/PARylation/K376 ubiquitination assays; UDP-glucuronate binding with UGDH KO; OGT Co-IP and site mapping; acetylhypusination identification with NAT1-KO mice\",\n      \"pmids\": [\"39471814\", \"38272024\", \"37169760\", \"39276723\", \"39511379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy and cross-talk among these PTMs not integrated\", \"Most are single-lab biochemical characterizations\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked RIPK1 to nuclear-envelope necroptosis and inflammatory feed-forward circuits, with prelamin A recruiting RIPK1 to drive nuclear MLKL activation and a RIPK1/JAK1/RIPK3\\u2013STAT1 complex sustaining alloreactive T cell responses in GVHD.\",\n      \"evidence\": \"Prelamin A\\u2013RIPK1 nuclear Co-IP with RIPK3/MLKL rescue in Zmpste24-/- mice; RIPK1/RIPK3\\u2013JAK1 Co-IP and STAT1 assays with IEC conditional KO in HSCT model\",\n      \"pmids\": [\"38538837\", \"36356302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of nuclear-envelope necroptosis beyond progeroid context unclear\", \"Direct vs assembled-complex contribution of RIPK1 to STAT1 activation not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many parallel inhibitory and activating modifications are integrated in space and time on a single RIPK1 molecule to set the survival/inflammation/death threshold remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model ordering the PTM checkpoints\", \"Structure of full-length RIPK1 in complex I/II not determined\", \"Triggers for nuclear vs cytosolic RIPK1 functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [15, 26]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [9, 11, 15, 26]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 7, 21]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [15, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [15, 28]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [28]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 2, 7, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 20, 27, 35]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 14, 25]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [9, 13, 24]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [\n      \"TNFR1 signaling complex (complex I)\",\n      \"complex II / necrosome\",\n      \"BAF chromatin-remodeling complex\",\n      \"Rag-Ragulator supercomplex\"\n    ],\n    \"partners\": [\n      \"RIPK3\",\n      \"FADD\",\n      \"CASP8\",\n      \"TBK1\",\n      \"TRAF2\",\n      \"ZBP1\",\n      \"JAK1\",\n      \"OTUD1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}