Affinage

RIPK1

Receptor-interacting serine/threonine-protein kinase 1 · UniProt Q13546

Length
671 aa
Mass
75.9 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RIPK1 is a serine/threonine kinase that serves as a central signaling hub at the crossroads of cell survival, apoptosis, and necroptosis downstream of TNFR1 and related death receptors. In its kinase-independent scaffold capacity, RIPK1 promotes NF-κB-dependent survival signaling, stabilizes TRAF2, and facilitates AMPK–TSC2 interaction to restrain mTORC1 during energy stress; loss of RIPK1 scaffold function triggers both FADD/caspase-8-dependent apoptosis and RIPK3/MLKL-dependent necroptosis in vivo (PMID:25132550, PMID:24813850, PMID:33271062). RIPK1 kinase activation requires death-domain-mediated dimerization, S161 autophosphorylation driven by mitochondrial ROS sensing, K63-ubiquitination-dependent DHHC5-mediated palmitoylation, and PP1γ/PPP6C-catalyzed removal of inhibitory phosphorylations, while MK2 (Ser321), AMPK (Ser415), JAK1/SRC (Tyr384), and caspase-8 cleavage at Asp325 each act as checkpoints that suppress kinase activation and death complex assembly (PMID:28176780, PMID:29440439, PMID:39471814, PMID:28506461, PMID:37384704, PMID:36329033, PMID:31511692). Heterozygous human mutations preventing caspase-8 cleavage of RIPK1 (D324N/H/Y) cause a periodic fever autoinflammatory syndrome driven by unopposed RIPK1-kinase-dependent apoptosis and necroptosis (PMID:31827281).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2011 High

    Establishing that RIPK1 and FADD operate in an epistatic circuit controlling embryonic viability resolved the question of whether RIPK1 promotes or restrains cell death in vivo — it does both, depending on cell type and co-factor availability.

    Evidence Double-knockout (Fadd−/−Rip1−/−) mouse genetics with T cell death assays and NF-κB reporters

    PMID:21368761

    Open questions at the time
    • Kinase-dependent vs kinase-independent contributions not separated
    • Contribution of RIPK3/necroptosis arm not genetically tested
  2. 2011 Medium

    Identification of USP2a as a deubiquitinase removing K63-linked ubiquitin from RIP1 within the TNFR1 complex revealed that dynamic ubiquitin editing controls the transition from pro-survival complex I to pro-death complex II.

    Evidence USP2a knockdown/overexpression with TNFR1 complex co-IP and ubiquitin chain-type analysis

    PMID:22179575

    Open questions at the time
    • Single-lab observation without independent replication
    • Relative contributions of USP2a vs CYLD to RIP1 deubiquitination not compared
  3. 2012 Medium

    Demonstrating that cIAP1/2 limit necrosome formation by controlling RIP3 expression levels, rather than solely through direct RIP1 ubiquitination, broadened understanding of how IAPs suppress necroptosis.

    Evidence cIAP1/2 KO macrophages with necrosome co-IP and RIP3 knockdown rescue

    PMID:22576661

    Open questions at the time
    • Post-transcriptional mechanism for RIP3 regulation not defined
    • Contribution of LUBAC-dependent linear ubiquitination not addressed
  4. 2013 Medium

    Mapping Ser89 as an inhibitory phosphoacceptor in the RIPK1 kinase domain showed that tonic phosphorylation restrains kinase activity, introducing the concept that multiple inhibitory phosphosites gate RIPK1 activation.

    Evidence Site-directed mutagenesis (S89A) with kinase activity assays and TNF-induced necrosis

    PMID:24059293

    Open questions at the time
    • Upstream kinase responsible for S89 phosphorylation not identified
    • Single-lab study
  5. 2014 High

    Genetic separation of RIPK1's kinase-independent scaffold function from cell death demonstrated that RIPK1 concurrently blocks caspase-8-dependent apoptosis and RIPK3-dependent necroptosis to maintain tissue homeostasis, particularly in intestinal epithelium.

    Evidence IEC-specific RIPK1 KO combined with FADD, RIPK3, TNFR1 KO epistasis in mice; triple/quadruple whole-body KO mice

    PMID:24813850 PMID:25132550

    Open questions at the time
    • Molecular mechanism by which scaffold inhibits spontaneous RIPK3 oligomerization undefined
    • Cell-type differences in scaffold dependency not fully mapped
  6. 2014 High

    Reconstitution of RIPK1's dual role — activating RIPK3 via RHIM engagement yet suppressing spontaneous RIPK3 oligomerization — clarified why RIPK1 can be either pro-death or pro-survival depending on context.

    Evidence Inducible RIPK3 dimerization/oligomerization constructs in RIPK1-KO cells, kinase-dead RIPK1 rescue

    PMID:24902904

    Open questions at the time
    • Stoichiometric requirements for RIPK1-RIPK3 RHIM heteromers vs RIPK3 homo-oligomers not defined
  7. 2016 High

    Discovery that ZBP1 competes with RIPK1 for RIPK3 RHIM engagement established that the RIPK1 RHIM domain acts as a molecular shield preventing ZBP1-driven necroptosis, explaining perinatal lethality of RIPK1 RHIM-mutant mice.

    Evidence RHIM-mutant knock-in mice rescued by ZBP1/RIPK3/MLKL KO; co-IP of ZBP1–pRIPK3 in RIPK1-RHIM-mutant cells

    PMID:27819681

    Open questions at the time
    • Endogenous ligand activating ZBP1 in this context not identified
    • Whether RHIM competition is purely stoichiometric or regulated remains unclear
  8. 2016 Medium

    Demonstration that RIPK1 stabilizes TRAF2 and that combined RIPK1/TRAF2 loss in liver drives NF-κB failure and spontaneous hepatocellular carcinoma connected RIPK1 scaffold function to tumor suppression.

    Evidence Liver-specific RIPK1 and RIPK1/TRAF2 double-KO mice with TRAF2 degradation assays and NF-κB activity measurement

    PMID:28017612

    Open questions at the time
    • Mechanism by which RIPK1 prevents TRAF2 proteasomal degradation not elucidated
    • Single-lab study
  9. 2016 High

    Linking optineurin to RIPK1 turnover revealed that impaired RIPK1 degradation drives progressive axonal degeneration via the RIPK1–RIPK3–MLKL necroptotic axis, connecting RIPK1 to neurodegeneration.

    Evidence OPTN-KO mouse with RIPK1/RIPK3 pathway inhibition rescue; human ALS tissue analysis

    PMID:27493188

    Open questions at the time
    • Exact ubiquitin ligase/proteasomal pathway through which OPTN promotes RIPK1 turnover not defined
  10. 2017 High

    Three independent studies converged to show that MK2 directly phosphorylates RIPK1 at Ser321, providing the first identified inhibitory kinase checkpoint on cytosolic RIPK1 that prevents death complex assembly downstream of TNF.

    Evidence In vitro kinase assays, phospho-mimetic/dead mutagenesis, MK2-KO mouse with TNF-SIRS model

    PMID:28506461 PMID:28920952

    Open questions at the time
    • Whether other MK2 sites on RIPK1 contribute was not fully resolved
    • Integration with other inhibitory phosphorylations (S89, Y384) not tested
  11. 2017 High

    Identification of ROS-sensing cysteines and S161 autophosphorylation as prerequisites for RIPK3 recruitment to the necrosome established that RIPK1 kinase activation is gated by redox sensing.

    Evidence Site-directed mutagenesis, in vitro kinase assay, ROS manipulation, co-IP of RIP1–RIP3

    PMID:28176780

    Open questions at the time
    • Identity and chemical nature of the ROS species sensed by these cysteines not defined
    • Whether S161 autophosphorylation is constitutive or stimulus-specific not resolved
  12. 2017 High

    Showing that the SPATA2–CYLD complex preferentially cleaves M1/linear ubiquitin chains on RIPK1 within the TNF-RSC revealed how deubiquitination specifically enables RIPK1 kinase activation at complex I.

    Evidence SPATA2-KO cells, in vitro reconstituted CYLD–SPATA2 deubiquitination assay, TNF-RSC pulldown, mouse TNF-SIRS model

    PMID:28701375

    Open questions at the time
    • Relative timing of M1 vs K63 chain removal not resolved
    • Whether SPATA2-independent CYLD activity on RIPK1 is physiologically relevant unclear
  13. 2018 High

    Establishing that death-domain-mediated RIPK1 dimerization is required for kinase activation — and that forced dimerization bypasses a point mutation blocking it — defined the molecular trigger for RIPK1 kinase engagement.

    Evidence K584R knock-in mice, forced dimerization constructs, complex II co-IP, TNF-SIRS model

    PMID:29440439

    Open questions at the time
    • Whether DD dimerization precedes or follows ubiquitin editing at complex I not resolved
    • Structural basis of DD-mediated dimer interface not determined
  14. 2019 High

    Human patients with heterozygous RIPK1 D324 mutations and Ripk1-D325A knock-in mice demonstrated that caspase-8 cleavage of RIPK1 is an essential physiological brake: its loss causes embryonic lethality in mice and periodic fever autoinflammatory disease in humans.

    Evidence Human genetic studies (D324N/H/Y families), knock-in mouse (D325A), epistasis with TNFR1/RIPK3/MLKL/Casp8 KOs

    PMID:31511692 PMID:31827281

    Open questions at the time
    • Whether partial cleavage resistance (heterozygous human) operates through haploinsufficiency or dominant-negative mechanism not fully resolved
  15. 2020 Medium

    Discovery that RIPK1 scaffolds the AMPK–TSC2 interaction to restrain mTORC1 during energy stress placed RIPK1 in metabolic sensing, explaining why RIPK1-deficient cells accumulate defective lysosomes and RIPK3/CASP8.

    Evidence RIPK1-KO cells and mice, AMPK–TSC2 co-IP, TSC2 phosphorylation at S1387, mTORC1 readouts

    PMID:33271062

    Open questions at the time
    • Single-lab observation
    • Whether RIPK1 directly contacts AMPK or TSC2 not resolved
    • Structural basis of scaffold function in this context unknown
  16. 2021 High

    A genome-wide CRISPR screen identified PP1γ (recruited by PPP1R3G) as the phosphatase that removes inhibitory Ser25 phosphorylation from RIPK1 at complex I, answering how pro-death signaling overcomes IKKε/TBK1-mediated inhibition.

    Evidence CRISPR KO screen, PPP1R3G mutant unable to bind PP1γ, phospho-S25 mutagenesis, Ppp1r3g-KO mouse protected from TNF-SIRS

    PMID:34862394

    Open questions at the time
    • Whether PP1γ removes other inhibitory phosphosites (S321, S415) not tested
    • Temporal regulation of PPP1R3G recruitment to complex I not defined
  17. 2022 High

    Super-resolution imaging directly visualized necrosome architecture: RIPK1 autophosphorylation drives ordered oligomerization into round-to-rod-shaped mosaic structures with RIPK3, and RIPK3 oligomers ≥tetramer recruit MLKL, providing the first structural framework for necrosome assembly.

    Evidence Super-resolution microscopy, RIPK1 autophosphorylation mutants, forced oligomerization constructs

    PMID:35256774

    Open questions at the time
    • Atomic-resolution structure of the mosaic necrosome not available
    • How membrane association influences rod formation not addressed
  18. 2022 High

    Identification of JAK1/SRC-mediated Tyr384 phosphorylation as an inhibitory checkpoint on RIPK1 — with Y383F knock-in mice developing systemic inflammation — expanded the repertoire of kinases restraining RIPK1 and connected it to cytokine receptor signaling.

    Evidence In vitro kinase assay (JAK1/SRC), Y383F knock-in mouse, genetic epistasis with TNFR1/RIPK3/Casp8 KO

    PMID:36329033

    Open questions at the time
    • Relative contribution of JAK1 vs SRC in different tissues not resolved
    • Whether Y384 phosphorylation is constitutive or stimulus-induced in vivo not clear
  19. 2022 High

    Showing that SENP1-mediated deSUMOylation of RIPK1 within the TNF-RSC prevents aberrant ubiquitination and kinase activation introduced SUMOylation as an additional post-translational layer regulating RIPK1.

    Evidence Hepatocyte-specific SENP1-KO mouse, biochemical characterization of RIPK1 SUMOylation/ubiquitination changes, RIPK1 kinase-dead rescue

    PMID:36414671

    Open questions at the time
    • SUMO E3 ligase responsible for RIPK1 SUMOylation not identified
    • SUMOylation sites on RIPK1 not mapped
  20. 2023 High

    AMPK phosphorylation of RIPK1 at Ser415 linked metabolic energy sensing directly to RIPK1 kinase inhibition, explaining how energy depletion (e.g., ischemia) tips RIPK1 toward activation when AMPK is lost.

    Evidence In vitro kinase assay, S415A knock-in mouse, myeloid Ampkα1-KO with RIPK1 inactivation rescue in ischemia model

    PMID:37384704

    Open questions at the time
    • Whether AMPK-S415 and MK2-S321 phosphorylations are cooperative or redundant not tested
    • Relevance in non-myeloid tissues not explored
  21. 2023 Medium

    A non-necroptotic RIPK1/RIPK3–JAK1–STAT1 signaling axis in intestinal epithelial cells promoting MHC-II expression revealed a death-independent inflammatory function of RIPK1.

    Evidence Co-IP of RIPK1/RIPK3–JAK1 complex, IEC-specific conditional KOs, STAT1 phosphorylation assays, GVHD model

    PMID:36356302

    Open questions at the time
    • Whether RIPK1 kinase activity is required for JAK1 complex formation not tested
    • Single-lab observation
    • Mechanism of RIPK1–JAK1 interaction not defined
  22. 2024 High

    Discovery that DHHC5-mediated S-palmitoylation of RIPK1, dependent on prior K63-ubiquitination, licenses kinase-domain homo-interaction and activation connected lipid metabolism to RIPK1 cytotoxicity in steatohepatitis.

    Evidence Palmitoylation assay, DHHC5 KO/overexpression, ubiquitination–palmitoylation epistasis, kinase domain interaction studies, MASH mouse model

    PMID:39471814

    Open questions at the time
    • Palmitoylation site(s) on RIPK1 not fully mapped
    • Whether palmitoylation is reversible and by which thioesterase not addressed
  23. 2024 Medium

    Identification of the PP6 holoenzyme (PPP6C) as a phosphatase promoting pro-death S166 autophosphorylation while reducing inhibitory S321 phosphorylation expanded the phosphatase repertoire controlling RIPK1 activation beyond PP1γ.

    Evidence CRISPR cell death screen, PPP6C KO, phospho-S166/S321 RIPK1 western blotting, PANoptosis assays

    PMID:38807188

    Open questions at the time
    • Whether PPP6C acts directly on RIPK1 or through intermediate kinase/phosphatase not formally excluded
    • Single-lab CRISPR screen without independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full structural model of the RIPK1 necrosome at atomic resolution, the precise ordering and cooperativity among multiple inhibitory phosphorylations (S25, S89, S321, S415, Y384), and the mechanism by which RIPK1 scaffold function restrains spontaneous RIPK3 oligomerization remain unresolved.
  • No high-resolution cryo-EM/crystal structure of the full-length RIPK1-RIPK3 necrosome
  • Integrated quantitative model of inhibitory phosphorylation hierarchy absent
  • Structural basis of scaffold-mediated RIPK3 suppression unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 4 GO:0005886 plasma membrane 3
Pathway
R-HSA-5357801 Programmed Cell Death 9 R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3
Partners
CASP8CYLDDHHC5FADDJAK1MLKLRIPK3ZBP1
Complex memberships
Complex II (RIPK1-FADD-caspase-8)Necrosome (RIPK1-RIPK3)TNF-RSC (complex I)

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 RIP1 autophosphorylates at serine 161 (S161) in response to mitochondrial ROS sensed via three crucial cysteines in RIP1; this S161 autophosphorylation is required for RIP3 recruitment to form a functional necrosome during TNF-induced necroptosis. Site-directed mutagenesis, in vitro kinase assay, ROS manipulation, co-immunoprecipitation of RIP1-RIP3 complex Nature Communications High 28176780
2019 Caspase-8 cleaves RIPK1 at Asp325, and knock-in mice expressing cleavage-resistant RIPK1(D325A) die mid-gestation from TNF/RIPK1-kinase/FADD-caspase-8-driven cell death, demonstrating that caspase-8 cleavage of RIPK1 is essential to dismantle death-inducing complexes and limit apoptosis. Knock-in mouse genetics (D325A mutation), genetic epistasis (TNFR1 KO, MLKL KO, FADD KO rescue), biochemical detection of cleaved caspase-3 Nature High 31511692
2019 Heterozygous missense mutations (D324N, D324H, D324Y) in human RIPK1 prevent caspase-8 cleavage at this site, causing hyperactivation of RIPK3-dependent apoptosis and necroptosis and resulting in a periodic fever autoinflammatory syndrome; mouse Ripk1D325A/D325A embryonic lethality is fully rescued only by combined loss of Casp8 and Ripk3. Human genetic analysis, Ripk1D325A knock-in mouse, epistasis with Ripk3/Mlkl/Casp8 knockouts, cell death assays Nature High 31827281
2017 MK2 directly phosphorylates RIPK1 at Ser321, inhibiting RIPK1 kinase activation and its ability to bind FADD/caspase-8, thereby suppressing TNF-induced RIPK1-kinase-dependent apoptosis and necroptosis; a phosphomimetic S321D mutation limits TNF-induced death. In vitro kinase assay (MK2 phosphorylates RIPK1), phospho-mimetic/phospho-dead mutagenesis, co-immunoprecipitation, MK2-KO mouse model Molecular Cell High 28506461 28920952
2017 MK2 phosphorylates RIPK1 to limit cytosolic activation of RIPK1 and subsequent assembly of the death complex; MK2 inactivation sensitizes mice to TNF-induced cytotoxic shock in a RIPK1-kinase-dependent manner. Direct substrate identification by in vitro kinase assay, mouse model of sterile shock, RIPK1 phosphorylation site analysis Nature Cell Biology High 28920952
2016 RIPK1 prevents ZBP1-mediated RIPK3-MLKL-dependent necroptosis in keratinocytes through its RHIM domain; mutation of the RIPK1 RHIM (RIPK1mRHIM) causes perinatal lethality rescued by ZBP1, RIPK3, or MLKL deficiency, and ZBP1 interacts strongly with phosphorylated RIPK3 in RIPK1mRHIM cells. RHIM-mutant knock-in mice, genetic epistasis (ZBP1/RIPK3/MLKL KO), co-immunoprecipitation of ZBP1-pRIPK3 Nature High 27819681
2014 RIPK1 has kinase-independent scaffolding functions that prevent intestinal epithelial cell apoptosis and necroptosis; IEC-specific RIPK1 KO causes apoptosis rescued by FADD ablation, but double RIPK1/FADD KO leads to RIPK3-dependent necroptosis, establishing RIPK1 scaffold as a master regulator of epithelial survival. Conditional KO mouse models (IEC-specific), genetic epistasis (FADD, RIPK3, TNFR1 KO), histopathology Nature High 25132550
2014 RIPK1 blocks early postnatal lethality by inhibiting both caspase-8-dependent apoptosis and RIPK3-dependent necroptosis; animals lacking RIPK1, RIPK3, and either caspase-8 or FADD survive normally, while TNFR1 loss also rescues lethality, establishing RIPK1 as a negative regulator of both TNFR-induced apoptosis and TRIF/IFNAR-induced RIPK3 necroptosis. Triple/quadruple knockout mouse genetics, genetic epistasis, in vitro cell death assays Cell High 24813850
2011 RIPK1 deficiency allows normal embryogenesis of FADD-knockout mice and rescues FADD-KO embryonic necrosis, while FADD deletion corrects developmental defects of RIPK1-KO lymphocytes; FADD-KO/RIPK1-KO T cells resist Fas/TNF-induced death and show reduced NF-κB activity, demonstrating an in vivo cell-type-specific interplay between FADD and RIPK1 in apoptosis/necrosis regulation. Double-knockout mouse genetics (Fadd-/-Rip1-/-), embryonic rescue experiments, T cell death assays, NF-κB reporter Nature High 21368761
2018 RIPK1 death domain (DD) mediates RIPK1 dimerization that is required for kinase activation; a charge-conserved K584R mutation in the murine RIPK1 DD blocks RIPK1 activation, necroptosis, RIPK1-dependent apoptosis, and complex II formation, and protects mice from TNFα-induced SIRS; forced RIPK1 dimerization overcomes K584R resistance. Knock-in mutagenesis (K584R), forced dimerization constructs, co-immunoprecipitation (complex II), murine SIRS model PNAS High 29440439
2016 Optineurin (OPTN) suppresses RIPK1-dependent signaling by regulating RIPK1 turnover; loss of OPTN leads to progressive dysmyelination and axonal degeneration through RIPK1, RIPK3, and MLKL necroptotic machinery. OPTN-KO mouse model, genetic rescue with RIPK1/RIPK3 inhibition, human ALS pathological sample analysis Science High 27493188
2023 AMPK phosphorylates RIPK1 at Ser415 to inhibit RIPK1 activation during metabolic/energy stress; RIPK1 S415A mutation or AMPK deficiency promotes RIPK1 activation and cell death; genetic RIPK1 inactivation protects against ischemic injury in myeloid Ampkα1-deficient mice. In vitro kinase assay (AMPK phosphorylates RIPK1-S415), knock-in mouse (S415A), Ampk-KO mouse, ischemia model Science High 37384704
2021 PPP1R3G recruits its catalytic subunit PP1γ to complex I to dephosphorylate inhibitory phosphorylations on RIPK1 (including Ser25), thereby 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, PP1γ-PPP1R3G complex characterization, phospho-site mutagenesis (S25A), KO mouse Nature Communications High 34862394
2022 JAK1 and SRC tyrosine kinases phosphorylate RIPK1 at Y384 (Y383 in mouse), suppressing TNF-induced cell death; Ripk1Y383F/Y383F knock-in mice develop systemic inflammation and emergency haematopoiesis, rescued by RIPK1 kinase inhibition or upstream pathway deletions (TNFR1 KO or RIPK3/Casp8 double KO). In vitro kinase assay (JAK1/SRC phosphorylate RIPK1-Y384), knock-in mouse (Y383F), genetic epistasis with TNFR1/RIPK3/Casp8 KO Nature Communications High 36329033
2022 SENP1 deSUMOylates RIPK1 in the TNF-R1 signaling complex (TNF-RSC), keeping RIPK1 in check; SENP1 deficiency leads to RIPK1 SUMOylation, which re-orchestrates TNF-RSC and modulates ubiquitination patterns and kinase activity of RIPK1, promoting RIPK1-kinase-dependent apoptosis. Hepatocyte-specific SENP1-KO mouse, biochemical characterization of RIPK1 SUMOylation/ubiquitination changes, RIPK1 kinase-dead rescue Nature Communications High 36414671
2024 DHHC5-mediated S-palmitoylation of RIPK1 licenses its kinase activity by promoting homo-interaction of its kinase domain; this palmitoylation is dependent on K63-linked ubiquitination of RIPK1 and is induced by TNF; DHHC5 amplification in fatty-acid-rich conditions increases RIPK1 cytotoxicity in steatohepatitis. Palmitoylation assay, DHHC5 KO/overexpression, ubiquitination-palmitoylation epistasis, kinase domain interaction studies, mouse model (MASH) Molecular Cell High 39471814
2022 Super-resolution microscopy reveals that RIP1 and RIP3 form mosaic oligomeric necrosomes: initial complexes are round and large complexes are rod-shaped. RIP3 oligomers ≥tetramer recruit MLKL via phosphorylated RIP3. RIP1 autophosphorylation controls ordered RIP1 oligomerization and is required for RIP1-initiated RIP3 homo-oligomerization into functional rod-shaped mosaics for both necroptosis and apoptosis. Super-resolution microscopy (direct visualization), RIPK1 autophosphorylation mutants, forced oligomerization constructs Nature Cell Biology High 35256774
2016 Necroptotic RIP1 ubiquitination within the necrosome requires RIP1 kinase activity but not RIP3 or MLKL; mutation of a necroptosis-related ubiquitination site on RIP1 reduces necroptotic cell death and disrupts RIP1-RIP3 necrosome assembly; RIP1 ubiquitination is also detected in ischemia-reperfusion-injured kidneys. Immunoaffinity enrichment and mass spectrometry (ubiquitin site mapping), site mutagenesis, kinase-dead constructs, co-IP of necrosome, in vivo kidney injury model Cell Death and Differentiation High 27518435
2017 SPATA2 recruits CYLD to the TNF-RSC and promotes deubiquitination of M1 (linear) ubiquitin chains on RIPK1; SPATA2 deficiency promotes M1 ubiquitination of RIPK1 and inhibits RIPK1 kinase activity; the CYLD USP domain–SPATA2 PUB domain complex preferentially cleaves M1 ubiquitin chains in vitro. SPATA2-KO cells, in vitro deubiquitination assay (CYLD-SPATA2 complex on M1 chains), TNF-RSC pulldown, mouse TNF-SIRS model Genes & Development High 28701375
2014 RIPK1 both positively and negatively regulates RIPK3 oligomerization: it activates RIPK3 via RHIM-domain interactions in response to TNF-receptor signaling, but also suppresses spontaneous cytosolic RIPK3 oligomerization and death; catalytically inactive or chemically inhibited RIPK1 protects against spontaneous RIPK3 activation. Inducible dimerization/oligomerization constructs of RIPK3, RIPK1-KO cells, kinase-dead RIPK1 constructs, RHIM mutants Cell Death and Differentiation High 24902904
2011 De-ubiquitinating protease USP2a removes K63-linked ubiquitin chains from RIP1 (and TRAF2) in the TNFR1 complex; USP2a-mediated deubiquitination of RIP1 is required for efficient IκBα reappearance and NF-κB inactivation, converting complex I to pro-apoptotic complex II. USP2a knockdown/overexpression, co-immunoprecipitation of TNFR1 complex, ubiquitin chain-type analysis, NF-κB reporter assay Cell Death and Differentiation Medium 22179575
2015 HIV-1 protease cleaves RIPK1 at a defined site; a mutation at this cleavage site renders RIPK1 resistant to HIV-1 PR cleavage; cleavage of RIPK1 disrupts RIPK1/RIPK3 complex formation and RIPK1-mediated NF-κB induction during HIV-1 infection. In vitro HIV-1 protease cleavage assay, mutagenesis of cleavage site, co-immunoprecipitation (RIPK1-RIPK3), NF-κB reporter, HIV infection of T cells Retrovirology Medium 26297639
2020 RIPK1 scaffolding function (kinase-independent) promotes the AMPK-TSC2 interaction, facilitating TSC2 phosphorylation at Ser1387 and thereby inhibiting mTORC1 during energetic stress; RIPK1 loss results in high basal mTORC1 activity, defective lysosomes, RIPK3/CASP8 accumulation, and vulnerability to low glucose. RIPK1-KO cells and mice, co-immunoprecipitation (AMPK-TSC2), TSC2 phosphorylation assays, mTORC1 activity readouts, lysosome function assays Molecular Cell Medium 33271062
2013 Ser89 in the kinase domain of RIP1 is an inhibitory phosphoacceptor site: S89A substitution enhances RIP1 kinase activity and TNF-induced programmed necrosis without affecting necrosome formation. A phosphomimetic RIP3 S204D mutant induces necrosis independently of RIP1, indicating positive regulatory phosphorylation also controls necroptosis. Site-directed mutagenesis of RIP1 and RIP3 phosphosites, kinase activity assays, TNF-induced necrosis assay, necrosome co-IP Biochemical Journal Medium 24059293
2020 The RIPK1 platform (scaffold) function rather than its kinase activity mediates acetaminophen-induced hepatocyte death; RIPK1HepCKO mice are protected while RIPK1D138N (kinase-dead) mice are not; protection involves A20 upregulation which co-immunoprecipitates with both RIPK1 and ASK1, and RIPK1 presence reduces A20-ASK1 association, limiting JNK activation. Hepatocyte-specific RIPK1 KO vs kinase-dead knock-in mice, co-immunoprecipitation (A20-RIPK1-ASK1), JNK/pJNK assays, APAP liver injury model Journal of Biological Chemistry Medium 33460648
2017 RARγ (retinoic acid receptor gamma) is released from the nucleus to the cytoplasm to initiate formation of RIPK1-dependent death complexes by mediating RIP1 dissociation from TNFR1 when cIAP activity is blocked. shRNA screen (identified RARγ), co-immunoprecipitation of TNFR1 complex, nuclear/cytoplasmic fractionation, in vivo TNF necroptosis model Nature Communications Medium 28871172
2023 RIPK1/RIPK3 forms a complex with JAK1 to promote STAT1 activation in intestinal epithelial cells; RIPK1 and RIPK3 cooperate to drive MHC class II and chemokine production in an MLKL-independent but JAK/STAT1-dependent manner, creating a feed-forward inflammatory cascade amplified by IFNγ. Co-immunoprecipitation (RIPK1/RIPK3-JAK1 complex), IEC-specific conditional KOs, STAT1 phosphorylation assays, murine GVHD model Blood Medium 36356302
2024 PP6 holoenzyme (PPP6C plus regulatory subunits PPP6R1/R2/R3) promotes pro-death S166 autophosphorylation of RIPK1 and reduces pro-survival S321 phosphorylation, enabling TAK1-inhibitor-induced PANoptosis; loss of PPP6C significantly reduces RIPK1-dependent cell death. CRISPR cell death screen, PPP6C KO, phospho-S166 and phospho-S321 RIPK1 western blotting, PANoptosis assays BMC Biology Medium 38807188
2012 cIAP1 regulates RIP1 recruitment to the necrosome without directly altering RIP1 ubiquitination; both cIAP1 and cIAP2 limit RIP3 (and to lesser extent RIP1) expression via post-transcriptional mechanisms, thereby suppressing Rip1-Rip3 necrosome assembly and necroptosis. cIAP1/2 KO macrophages, RIP3 knockdown, Necrostatin-1 inhibition, necrosome co-IP, SM treatment Cell Death and Differentiation Medium 22576661
2016 Loss of RIPK1 in liver parenchymal cells induces TNF-dependent proteasomal degradation of TRAF2 in a kinase-independent manner, activating caspase-8; combined loss of RIPK1 and TRAF2 impairs NF-κB activation and promotes spontaneous hepatocellular carcinoma development. Liver-specific RIPK1 KO and RIPK1/TRAF2 double-KO mice, TRAF2 ubiquitination/degradation assays, caspase-8 activation, NF-κB reporter Cancer Cell Medium 28017612
2023 T cell-specific RIPK1 deficiency causes premature T cell senescence via higher basal mTORC1 activation; combined deficiency of RIPK3 and caspase-8 inhibition restores proliferative responses, mTORC1/AKT/ERK activation, caspase-3/7 activation, and senescence-related gene expression in RIPK1-deficient CD4 T cells. T cell-specific RIPK1 KO mice, RIPK3/Casp8 genetic rescue, mTORC1 inhibition (rapamycin), live cell imaging Science Advances Medium 36696505

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nature reviews. Neuroscience 768 30467385
2017 RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome. Nature communications 521 28176780
2016 RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science (New York, N.Y.) 510 27493188
2014 RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell 478 24813850
2014 RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 466 25132550
2019 Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis. Nature 440 31511692
2015 The diverse role of RIP kinases in necroptosis and inflammation. Nature immunology 439 26086143
2009 RIP kinases at the crossroads of cell death and survival. Cell 409 19632174
2010 The role of the kinases RIP1 and RIP3 in TNF-induced necrosis. Science signaling 381 20354226
2020 Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target. Nature reviews. Drug discovery 374 32669658
2011 Functional complementation between FADD and RIP1 in embryos and lymphocytes. Nature 360 21368761
2016 RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation. Nature 353 27819681
2019 Intratumoral activation of the necroptotic pathway components RIPK1 and RIPK3 potentiates antitumor immunity. Science immunology 327 31227597
2019 Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature 271 31827281
2017 MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death. Molecular cell 265 28506461
2014 RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis. Cell death and differentiation 244 24902904
2014 RIP kinases: key decision makers in cell death and innate immunity. Cell death and differentiation 199 25146926
2018 RIP kinases as modulators of inflammation and immunity. Nature immunology 198 30131615
2018 RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer. Cancer cell 195 30423296
2016 RIP: RNA Immunoprecipitation. Methods in molecular biology (Clifton, N.J.) 186 27659976
2013 Control of life-or-death decisions by RIP1 kinase. Annual review of physiology 182 24079414
2017 MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death. Nature cell biology 175 28920952
2020 RIPK1 Distinctly Regulates Yersinia-Induced Inflammatory Cell Death, PANoptosis. ImmunoHorizons 169 33310881
2000 Notch signal transduction: a real rip and more. Current opinion in genetics & development 158 10889061
2017 Complex Pathologic Roles of RIPK1 and RIPK3: Moving Beyond Necroptosis. Trends in pharmacological sciences 155 28126382
2018 Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases. Proceedings of the National Academy of Sciences of the United States of America 146 30591564
2010 Receptor-interacting protein (RIP) kinase family. Cellular & molecular immunology 145 20383176
2021 ZBP1 not RIPK1 mediates tumor necroptosis in breast cancer. Nature communications 144 33976222
2020 Inhibitors Targeting RIPK1/RIPK3: Old and New Drugs. Trends in pharmacological sciences 140 32035657
2016 RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer. Cancer cell 134 28017612
2019 RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases. Cell death and differentiation 129 31101885
2018 TWEAK and RIPK1 mediate a second wave of cell death during AKI. Proceedings of the National Academy of Sciences of the United States of America 129 29588419
2014 RIPK1- and RIPK3-induced cell death mode is determined by target availability. Cell death and differentiation 129 24902899
2012 cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation. Cell death and differentiation 128 22576661
2018 Death-domain dimerization-mediated activation of RIPK1 controls necroptosis and RIPK1-dependent apoptosis. Proceedings of the National Academy of Sciences of the United States of America 118 29440439
2013 Positive and negative phosphorylation regulates RIP1- and RIP3-induced programmed necrosis. The Biochemical journal 118 24059293
2021 RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis. Cell reports 105 33979622
2016 Coordinated ubiquitination and phosphorylation of RIP1 regulates necroptotic cell death. Cell death and differentiation 100 27518435
2015 Cellular IAP proteins and LUBAC differentially regulate necrosome-associated RIP1 ubiquitination. Cell death & disease 94 26111062
2011 IAPs: guardians of RIPK1. Cell death and differentiation 94 22095281
2022 Mosaic composition of RIP1-RIP3 signalling hub and its role in regulating cell death. Nature cell biology 87 35256774
2016 Necroptosis-independent signaling by the RIP kinases in inflammation. Cellular and molecular life sciences : CMLS 87 27048814
2023 Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1. Science (New York, N.Y.) 85 37384704
2023 Immune regulator IRF1 contributes to ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosome activation and inflammatory cell death (PANoptosis). The Journal of biological chemistry 81 37557956
2021 SARS-CoV-2 promotes RIPK1 activation to facilitate viral propagation. Cell research 79 34663909
2018 RIP Kinases in Liver Cell Death, Inflammation and Cancer. Trends in molecular medicine 71 30455045
2008 Presenilin: RIP and beyond. Seminars in cell & developmental biology 71 19073272
2013 Necrosis-dependent and independent signaling of the RIP kinases in inflammation. Cytokine & growth factor reviews 70 24412261
2011 De-ubiquitinating protease USP2a targets RIP1 and TRAF2 to mediate cell death by TNF. Cell death and differentiation 64 22179575
2020 Catalytically inactive RIP1 and RIP3 deficiency protect against acute ischemic stroke by inhibiting necroptosis and neuroinflammation. Cell death & disease 60 32703968
2021 A toolbox for imaging RIPK1, RIPK3, and MLKL in mouse and human cells. Cell death and differentiation 59 33589776
2022 SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation. Nature communications 58 36414671
2017 SPATA2 regulates the activation of RIPK1 by modulating linear ubiquitination. Genes & development 58 28701375
2021 Necrostatin-1 Prevents Ferroptosis in a RIPK1- and IDO-Independent Manner in Hepatocellular Carcinoma. Antioxidants (Basel, Switzerland) 56 34572979
2021 Genetic Regulation of RIPK1 and Necroptosis. Annual review of genetics 56 34813352
2020 Primidone blocks RIPK1-driven cell death and inflammation. Cell death and differentiation 50 33273695
2020 TRADD Mediates RIPK1-Independent Necroptosis Induced by Tumor Necrosis Factor. Frontiers in cell and developmental biology 49 32039207
2019 mTORC1 inhibition attenuates necroptosis through RIP1 inhibition-mediated TFEB activation. Biochimica et biophysica acta. Molecular basis of disease 49 31499159
2020 RIPK1 gene variants associate with obesity in humans and can be therapeutically silenced to reduce obesity in mice. Nature metabolism 45 32989316
2022 Advances in RIPK1 kinase inhibitors. Frontiers in pharmacology 43 36249746
2023 Targeting RIPK1 kinase for modulating inflammation in human diseases. Frontiers in immunology 41 36969188
2020 25 years of research put RIPK1 in the clinic. Seminars in cell & developmental biology 38 32938551
2014 Retaining MKP1 expression and attenuating JNK-mediated apoptosis by RIP1 for cisplatin resistance through miR-940 inhibition. Oncotarget 38 24675421
2022 Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation. Nature communications 35 36329033
2020 The diverse roles of RIP kinases in host-pathogen interactions. Seminars in cell & developmental biology 35 32859501
2020 The Role of RIPK1 and RIPK3 in Cardiovascular Disease. International journal of molecular sciences 35 33142926
2017 The cytoplasmic nuclear receptor RARγ controls RIP1 initiated cell death when cIAP activity is inhibited. Nature communications 35 28871172
2014 Assays for necroptosis and activity of RIP kinases. Methods in enzymology 35 25065884
2023 RIPK1 blocks T cell senescence mediated by RIPK3 and caspase-8. Science advances 34 36696505
2023 A novel RIPK1 inhibitor reduces GVHD in mice via a nonimmunosuppressive mechanism that restores intestinal homeostasis. Blood 33 36356302
2020 Regulatory mechanisms of RIPK1 in cell death and inflammation. Seminars in cell & developmental biology 33 32616439
2021 The latest information on the RIPK1 post-translational modifications and functions. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 31 34449307
2021 RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis. Nature communications 31 34862394
2020 RIPK1 Promotes Energy Sensing by the mTORC1 Pathway. Molecular cell 31 33271062
2015 HIV-1 protease cleaves the serine-threonine kinases RIPK1 and RIPK2. Retrovirology 31 26297639
2021 RIP1 Perturbation Induces Chondrocyte Necroptosis and Promotes Osteoarthritis Pathogenesis via Targeting BMP7. Frontiers in cell and developmental biology 30 33937236
2021 RIPK1 and TRADD Regulate TNF-Induced Signaling and Ripoptosome Formation. International journal of molecular sciences 30 34830347
2017 Dendritic Cell RIPK1 Maintains Immune Homeostasis by Preventing Inflammation and Autoimmunity. Journal of immunology (Baltimore, Md. : 1950) 30 29212904
2011 RIP1-mediated regulation of lymphocyte survival and death responses. Immunologic research 30 22038529
2021 Viral Suppression of RIPK1-Mediated Signaling. mBio 29 34372694
2012 NFκB and ubiquitination: partners in disarming RIPK1-mediated cell death. Immunologic research 29 22477525
2024 The protein phosphatase PP6 promotes RIPK1-dependent PANoptosis. BMC biology 28 38807188
2020 Cell-specific activation of RIPK1 and MLKL after intracerebral hemorrhage in mice. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 28 33210566
2019 Depletion of RIPK1 in hepatocytes exacerbates liver damage in fulminant viral hepatitis. Cell death & disease 28 30622241
2022 RIP1 post-translational modifications. The Biochemical journal 27 35522161
2020 Identification of MYC as an antinecroptotic protein that stifles RIPK1-RIPK3 complex formation. Proceedings of the National Academy of Sciences of the United States of America 27 32753382
2024 Palmitoylation licenses RIPK1 kinase activity and cytotoxicity in the TNF pathway. Molecular cell 26 39471814
2020 Constitutive Interferon Attenuates RIPK1/3-Mediated Cytokine Translation. Cell reports 26 31968247
2019 RIP1, RIP3, and MLKL Contribute to Cell Death Caused by Clostridium perfringens Enterotoxin. mBio 26 31848291
2015 RIP-Seq data analysis to determine RNA-protein associations. Methods in molecular biology (Clifton, N.J.) 26 25577386
2013 Profiling post-transcriptionally networked mRNA subsets using RIP-Chip and RIP-Seq. Methods (San Diego, Calif.) 24 24257445
2022 Microglial Dysfunction in Neurodegenerative Diseases via RIPK1 and ROS. Antioxidants (Basel, Switzerland) 22 36358573
2022 RIPK1 mutations causing infantile-onset IBD with inflammatory and fistulizing features. Frontiers in immunology 22 36466854
2020 COP9 Signalosome Suppresses RIPK1-RIPK3-Mediated Cardiomyocyte Necroptosis in Mice. Circulation. Heart failure 22 32578441
2024 Development of a RIPK1 degrader to enhance antitumor immunity. Nature communications 21 39681571
2021 Interaction of RIPK1 and A20 modulates MAPK signaling in murine acetaminophen toxicity. The Journal of biological chemistry 21 33460648
2021 Role of Receptor Interacting Protein (RIP) kinases in cancer. Genes & diseases 21 36157481
2020 RIPK1 ubiquitination: Evidence, correlations and the undefined. Seminars in cell & developmental biology 21 32980239
2019 Decreased RIPK1 expression in chondrocytes alleviates osteoarthritis via the TRIF/MyD88-RIPK1-TRAF2 negative feedback loop. Aging 21 31606726
2014 RIP1 modulates death receptor mediated apoptosis and autophagy in macrophages. Molecular oncology 21 25583602