RIPK1 (human, Q13546) — curation notes

Provenance note: Provider deep research for this gene failed (Falcon returned
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RIPK1-deep-research-<provider>.md file exists. This notes file is a manual
literature synthesis built from the UniProt record (RIPK1-uniprot.txt), the
cached publications in publications/, and cached Reactome entries, and it
replaces the provider deep research for this review.

Identity and architecture

• Receptor-interacting serine/threonine-protein kinase 1; 671 aa.
• N-terminal protein kinase domain (17-289; active-site proton acceptor D138),
  intermediate domain carrying the RIP homotypic interaction motif (RHIM,
  531-547), C-terminal death domain (DD, 583-669) (UniProt features).
• Caspase-8 cleavage site D324 separates the kinase domain from the
  intermediate domain and DD PMID:10521396.

Molecular function

• Ser/Thr protein kinase. "RIP is a serine-threonine kinase that is
  recruited by TRADD to TNFR1 in a TNF-dependent process" PMID:8612133.
  Crystal structures of the kinase domain with necrostatins: "Necrostatins, a
  series of small-molecule inhibitors, suppress necroptosis by specifically
  inhibiting RIP1 kinase activity" PMID:23473668. Autophosphorylation sites
  (S14/15, S20, S161, S166) are readouts of activation PMID:30988283.
• Known substrates are few: RIPK1 itself, RIPK3 (reciprocal phosphorylation
  within the necrosome) PMID:19524513,
  and DAB2IP/AIP1 Ser-604 PMID:17389591.
• Scaffold/adaptor (kinase-independent). In TNFR1 complex I RIPK1 is
  ubiquitinated (cIAP1/2, LUBAC) and recruits NEMO/IKK and TAB/TAK1, driving
  canonical NF-kB activation. "In contrast to its role in nuclear factor kappa B
  activation, RIP requires its own kinase activity for death signaling"
  PMID:11101870. "RIPK1 regulates cell death and inflammation through
  kinase-dependent and -independent mechanisms. As a scaffold, RIPK1 inhibits
  caspase-8-dependent apoptosis and RIPK3/MLKL-dependent necroptosis. As a
  kinase, RIPK1 paradoxically induces these cell death modalities."
  PMID:30988283. RIP interacts with IKKgamma via a region homologous to ABIN-2
  PMID:14653779;
  p62/SQSTM1 links RIP to aPKC PMID:10356400.
• Death-domain interactions. DD binds TRADD, FAS, TNFR1, FADD and CRADD
  [PMID:7538908; PMID:8612133; PMID:9044836 "a COOH-terminal DD that interacts with RIP"].
  DD-mediated homodimerization activates the kinase PMID:29440439.
• RHIM amyloid. RHIMs of RIP1 and RIP3 form hetero-amyloid fibrils required
  for necrosis PMID:22817896.

Complexes / locations

• Complex I (TNF-RSC), plasma-membrane-bound receptor complex
  PMID:12887920.
• Complex II / complex IIa (RIPK1-FADD-caspase-8) cytosolic
  [PMID:12887920; PMID:18485876; PMID:21525013].
• Ripoptosome: "RIP1 is the core component of the complex." PMID:21737330.
• Necrosome (complex IIb: RIPK1-RIPK3-MLKL), with PGAM5 PMID:22265414.
• Endosomal TNFR complexes (CARP-2 ubiquitinates RIP at endocytic vesicles)
  PMID:18450452.
• Cytoplasm/cytosol (UniProt; Reactome).

Biological processes

• Canonical NF-kB activation downstream of TNFR1 (scaffold).
  Overexpression induces NF-kB; DD alone is dominant negative PMID:8612133.
  Cleavage by caspase-8 abolishes NF-kB activation PMID:10521396.
• Pro-survival / anti-death (scaffold). Inhibits caspase-8 apoptosis and
  RIPK3/MLKL necroptosis PMID:30988283; in vivo scaffold function inhibits
  necroptosis in keratinocytes PMID:36380021.
  Caspase-8-resistant RIP protects against apoptosis in vitro PMID:10521396.
• Necroptosis (kinase-dependent). RIP kinase required for Fas/TNF/TRAIL
  caspase-independent death PMID:11101870; RIPK3 recruited to RIPK1 to form
  necrosis-inducing complex PMID:19524512; RIPK3 phosphorylates MLKL
  PMID:22265413. Necrostatin-1 blocks TNF/Smac mimetic necroptosis in FADD- or
  caspase-8-deficient cells PMID:22028622. In TNF signaling, caspase-8
  inactivation "switches the TNF response to RIPK1 kinase activity-dependent
  necroptosis, which additionally requires recruitment of the kinase RIPK3 and
  of the potential pore-forming pseudo-kinase mixed lineage kinase domain-like
  protein (MLKL) to complex II, now called the ‘necrosome’" PMID:36380021.
  RIPK1 is therefore an upstream activator; RIPK3 is the MLKL kinase.
• RIPK1-dependent apoptosis (kinase-dependent). Smac mimetic-induced
  caspase-8 activation requires RIPK1 PMID:18485876; TWEAK/autocrine TNF
  apoptosis PMID:21525013; IAP inhibitor + chemotherapy in ALL PMID:22173242;
  DNA-damage autocrine TNF loop PMID:21458669.
• Inflammation. Non-cleavable human RIPK1 D324V/H variants cause CRIA
  autoinflammatory disease with IL-6/TNF overproduction PMID:31827280.
  Ser25 phosphorylation by IKKs restrains kinase-dependent death PMID:30988283.
• Other: JNK/p38 activation via DAB2IP-ASK1 PMID:17389591; ROS
  [PMID:17979836 review]; ANT inhibition in necrosis PMID:16507998.

Curation issues identified

• GO:0004706 JUN kinase kinase kinase activity (IBA) and derived MAPK cascade:
  no evidence RIPK1 phosphorylates MAP2K4/MAP2K7.
• GO:0004722 protein serine/threonine phosphatase activity (IEA): RIPK1 is a
  kinase; phosphatase activity in the necrosome belongs to PGAM5
  PMID:22265414. Remove.
• GO:0070105 positive regulation of IL-6-mediated signaling: evidence
  PMID:31827280 is for IL-6 production, not IL-6 receptor signaling ->
  GO:0032755.
• GO:1903800 positive regulation of miRNA processing PMID:26020802: paper shows
  NF-kB-dependent miRNA induction, not processing.
• GO:0097300 programmed necrotic cell death: GO comment says use when RIPK1/RIPK3
  involvement not shown; necroptotic process is the appropriate term.
• 72 protein binding rows: uninformative; specific functions captured elsewhere.

Disease

• RIPK1 deficiency (biallelic LoF) causes immunodeficiency with
  early-onset IBD and arthritis; dominant non-cleavable variants cause CRIA
  PMID:31827280. RIPK1 kinase activity is implicated in neuroinflammation and
  neurodegeneration (not curated here in GO terms).