| 2019 |
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. |
Knock-in mouse models (RIPK1-D325A, caspase-8 catalytic mutants, MLKL-KO, FADD-KO, TNFR1-KO); embryo histology; genetic epistasis |
Nature |
High |
31511692
|
| 2019 |
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. |
Human genetic sequencing; knock-in mouse models (Ripk1D325A); cell death assays in patient-derived PBMCs and fibroblasts; genetic epistasis with Ripk3, Mlkl, Casp8 deletions |
Nature |
High |
31827280 31827281
|
| 2016 |
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. |
Knock-in mouse models (RIPK1-RHIM mutant); genetic rescue with ZBP1-KO, RIPK3-KO, MLKL-KO; Co-immunoprecipitation of ZBP1–RIPK3 complex |
Nature |
High |
27819681 27819682
|
| 2016 |
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. |
OPTN-knockout mice; pharmacological RIPK1 inhibition; histopathology of human ALS samples; genetic rescue with RIPK1/RIPK3 deficiency |
Science (New York, N.Y.) |
High |
27493188
|
| 2018 |
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. |
Biochemical reconstitution of TNFR1-SC; RIPK1 phosphorylation assays; TBK1/IKKε kinase-dead mutants; in vivo TNF shock model |
Nature cell biology |
High |
30420664
|
| 2018 |
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. |
Tbk1-/- mice rescued by RIPK1 kinase inhibition; Tbk1+/- aged mice with genetic/pharmacological RIPK1 inhibition; epistasis with TAK1 expression |
Cell |
High |
30146158
|
| 2014 |
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. |
Inducible dimerization/oligomerization RIPK3 constructs; RIPK1-KO and kinase-dead cells; necroptosis assays |
Cell death and differentiation |
Medium |
24902904
|
| 2019 |
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. |
Knock-in mouse model (RIPK1-K376R); pharmacological RIPK1 kinase inhibitor; genetic rescue with Fadd/Ripk3/Mlkl/Tnfr1 deletion; immunoprecipitation of complex II |
Nature communications |
High |
31519886 32999468
|
| 2021 |
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. |
Co-immunoprecipitation of OTUD1–RIPK1; ubiquitin linkage-specific deubiquitination assays; OTUD1-KO mice; bone marrow transplantation |
Cellular & molecular immunology |
Medium |
34876703
|
| 2023 |
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. |
In vitro kinase assays (AMPK phosphorylates RIPK1); knock-in RIPK1-S415A mice; Ampkα1-myeloid KO mice; ischemia model with genetic rescue |
Science (New York, N.Y.) |
High |
37384704
|
| 2020 |
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. |
In vitro kinase assay; mass spectrometry identification of ULK1 phosphorylation sites on RIPK1; siRNA knockdown; TNF-induced cell death assays; phosphomimetic mutants |
Cell reports |
Medium |
32320653
|
| 2022 |
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. |
In vitro kinase assay (JAK1/SRC phosphorylate RIPK1-Y384); knock-in mouse model (Ripk1-Y383F); genetic rescue; cell death assays |
Nature communications |
High |
36329033
|
| 2023 |
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. |
Hepatocyte-specific SENP1-KO mice; RIPK1 SUMOylation assays; TNF-RSC immunoprecipitation; rescue by RIPK1 kinase-dead knockin |
Nature communications |
Medium |
36414671
|
| 2023 |
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. |
Prolyl hydroxylation assays; pVHL co-immunoprecipitation; hepatocyte-specific Vhl-KO mice; EGLN1 inhibitor experiments; cell death assays under hypoxia |
Nature cell biology |
Medium |
37400498
|
| 2021 |
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. |
CRISPR whole-genome KO screen; Co-IP of PPP1R3G–PP1γ–RIPK1; PPP1R3G binding-mutant rescue; RIPK1-S25A mutation; Ppp1r3g-/- mice |
Nature communications |
High |
34862394
|
| 2022 |
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. |
Co-immunoprecipitation of nuclear RIPK1 with BAF; ChIP-seq for RIPK1 on H3K4me1/H3K27ac loci; phosphorylation assay for SMARCC2; nuclear fractionation; RIPK1 kinase inhibitor |
Cell research |
Medium |
35661830
|
| 2020 |
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. |
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 |
Molecular cell |
Medium |
33271062
|
| 2021 |
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. |
Genome-wide CRISPR screen; Co-immunoprecipitation of FADD/RIPK1/caspase-8 with Rag-Ragulator; Rag GTPase mutants; lysosomal tethering mutants; caspase-8 activity assays |
Science (New York, N.Y.) |
High |
35058659
|
| 2016 |
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. |
LPC-specific Ripk1/Traf2 conditional KO mice; TRAF2 ubiquitination/degradation assays; caspase-8 activity; TNF treatment; spontaneous tumor monitoring |
Cancer cell |
Medium |
28017612
|
| 2017 |
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. |
LPC-specific Ripk1/RelA double conditional KO; kinase-dead RIPK1 knock-in mice; DEN-induced liver tumor models; genetic rescue with TNFR1 deletion |
The Journal of clinical investigation |
Medium |
28628031
|
| 2016 |
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. |
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 |
Immunity |
Medium |
27396959
|
| 2024 |
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. |
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 |
Immunity |
High |
38744293
|
| 2024 |
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. |
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 |
Molecular cell |
Medium |
39471814
|
| 2024 |
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. |
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 |
Molecular cell |
Medium |
38272024
|
| 2024 |
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. |
Direct binding assay (UDP-glucuronate to RIPK1 kinase domain); UGDH conditional KO mice; rescue by RIPK1 kinase-dead knockin; metabolomic measurements |
Nature communications |
Medium |
37169760
|
| 2021 |
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. |
CRISPR genome-wide KO screen; Co-IP; PP1γ-binding mutant; RIPK1 S25A mutation; Ppp1r3g-/- mice |
Nature communications |
High |
34862394
|
| 2024 |
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. |
CRISPR cell death screen; genetic knockdown/KO of PP6 components; Western blot for RIPK1 pS166/pS321; TAK1 inhibitor-induced PANoptosis assay |
BMC biology |
Medium |
38807188
|
| 2022 |
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. |
Caspase-8 KO/inhibitor experiments; Co-IP of RIPK1–TBK1; IFN production assays; combined caspase-8/RIPK1 double-KO mice |
Cell reports |
Medium |
36198273
|
| 2024 |
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. |
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 |
Nature cell biology |
Medium |
38538837
|
| 2024 |
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. |
Solid-state NMR; structural determination of RIPK1 RHIM amyloid; mixing experiments with RIPK3 to form heterotypic fibrils |
Nature communications |
High |
39143113
|
| 2023 |
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. |
Co-IP of SMYD2–RIPK1; RIPK1 phosphorylation assays in SMYD2-deficient cells; SMYD2 pharmacological inhibition; in vivo tumor models |
Cell death & disease |
Medium |
35022391
|
| 2022 |
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. |
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 |
Immunity |
Medium |
35417675
|
| 2024 |
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. |
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 |
Drug resistance updates |
Medium |
39276723
|
| 2024 |
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. |
Identification of acetylhypusination modification on RIPK1; spermidine supplementation rescue; NAT1-KO mice; RIPK1 inhibitor in vivo; human diabetic vascular tissue analysis |
Nature cell biology |
Medium |
39511379
|
| 2021 |
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. |
T cell-specific RIPK1 conditional KO mice; combined RIPK3-KO and caspase-8 inhibition; mTORC1 activity measurement; senescence marker assays; proliferation assays |
Science advances |
Medium |
36696505
|
| 2024 |
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. |
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) |
Blood |
Medium |
36356302
|