RIPK3 (human, Q9Y572) — curation notes

Provenance note. Provider deep research for this gene FAILED (Falcon returned
HTTP 402 Payment Required; Perplexity was not configured). No
RIPK3-deep-research-<provider>.md file exists. The synthesis below replaces it and
was built from the UniProt record (RIPK3-uniprot.txt), the cached publications in
publications/, and cached Reactome entries. Quotes are verbatim from the cached
files.

Identity and architecture

• Receptor-interacting serine/threonine-protein kinase 3; 518 aa; N-terminal kinase
  domain and a unique C-terminal region containing the RIP homotypic interaction motif
  (RHIM; core tetrad VQVG).
  PMID:10358032
• Three isoforms (1, 2/beta, 3/gamma) per UniProt.

Core function: necroptotic kinase

• RIPK3 is required for TNF-induced programmed necrosis and its kinase activity is
  essential. PMID:19524512 PMID:19524512
• RIPK3 is recruited to RIPK1 to form the necrosis-inducing complex (necrosome).
  PMID:19524512 Reciprocal phosphorylation stabilises the complex.
  PMID:19524513
• Substrate: MLKL, phosphorylated on T357/S358 (human). PMID:22265413 Reactome R-HSA-5218906 ("RIPK3
  phosphorylates MLKL") records the same reaction.
• RIPK3 also phosphorylates RIPK1 (reciprocal auto/trans-phosphorylation; UniProt,
  citing PMID:19524513). PMID:19524513
• Activation-loop-region phosphorylation (T182) is needed for kinase activity and also
  creates a PELI1 degron. PMID:29883609

RHIM-mediated functional amyloid (necrosome scaffold)

• RIPK1 and RIPK3 RHIMs form hetero-amyloid fibrils required for kinase activation and
  necroptosis. PMID:22817896 PMID:22817896
• Solid-state NMR structure of the human RIPK1-RIPK3 core. PMID:29681455 PMID:29681455
• RIPK3 also forms homo-amyloid; cryo-EM structure of the RIPK3 RHIM fibril.
  PMID:33790016 Monomeric RHIM is intrinsically
  disordered. PMID:36870681
• Upstream RHIM partners besides RIPK1: ZBP1/DAI (UniProt; PMID:19590578) and TRIF
  (TLR3/4 pathway). Viral RHIM proteins (HSV-1 ICP6/R1, HSV-2 ICP10, MCMV M45) engage
  the RIPK3 RHIM and block necroptosis in human cells. PMID:26559832 PMID:33348174

Localisation

• Mainly cytosolic; forms punctae on necroptosis induction. PMID:22265413
• Shuttles through the nucleus; nuclear RIPK3 is kinase-active and contributes to
  cytosolic necrosome formation. PMID:30271893 PMID:30271893

Ripoptosome / apoptosis / NF-kB (secondary)

• In cIAP-depleted cells, the ripoptosome switches to RIP3-dependent necroptosis when
  caspase activity is low. PMID:21737330
• Early overexpression studies: RIPK3 C-terminus induces apoptosis and NF-kB
  activation; kinase domain dispensable for these. PMID:10339433 Conflicting: PMID:10358032 Its NF-kB activity is weak. PMID:21931591 These are overexpression phenotypes and are treated as non-core.

Antiviral defence

• RIP3-/- mice: impaired vaccinia-induced necrosis, inflammation, viral control.
  PMID:19524513

Curation judgements (summary)

• Core: protein serine/threonine kinase activity (MLKL, RIPK1 substrates); necroptotic
  signaling pathway / necroptotic process; component of ripoptosome/necrosome
  (GO:0097342, synonym "necrosome"); RHIM-driven amyloid assembly.
• Protein binding (GO:0005515) rows: all REMOVE per project policy (uninformative); the
  informative content (RIPK1 binding, self-association) is already captured by
  GO:0120283 and GO:0042802 rows.
• Mouse-derived IEA/ISS immune-development terms (thymus/spleen/lymph node development,
  T cell homeostasis, etc.) are phenotypes of compound mutants or indirect immune
  effects; marked as over-annotated.
• protein serine kinase activity (GO:0106310): RIPK3 phosphorylates both Thr and Ser on
  MLKL, so per the GO term's own usage note the dual term GO:0004674 is appropriate;
  MODIFY.
• "execution phase of necroptosis": RIPK3 acts upstream of the MLKL-driven execution
  phase; MODIFY to necroptotic signaling pathway.

Disease context

• RIPK3-dependent necroptosis is implicated in inflammatory tissue injury
  (pancreatitis model in PMID:19524512) and in neurodegeneration (PMID:29681455 abstract
  mentions neurodegenerative diseases). Not used for GO annotation.