Alt. symbols: RIP

Approved name: receptor interacting serine/threonine kinase 1
Alt. names: receptor (TNFRSF)-interacting serine-threonine kinase 1 | receptor-interacting protein kinase 1

Location: 6p25.2: 3063824 - 3115187 (+)
Gene type: protein_coding, 19 transcripts.

Scores: LoFtool: 0.387000 | pLI: 0.41817740 | LOEUF: 0.554

HGNC: 10019 | Infevers

NCBI: 8737, RefSeq: NG_063914.1

Ensembl: ENSG00000137275.16

LRG_ | Status: none

OMIM: 603453

Expression | ProteinAtlas

Gene Ontology (GO)

• Molecular function: JUN kinase kinase kinase activity [GO:0004706]
• Cell component:
• Biological process:

Normal function

RIPK1 encodes a a serine-threonine kinase that acts as an important regulator of TNF-induced activation of canonical NF-κB signaling and cell death. RIPK1 function is regulated by changes in post-translational modifications, including phosphorylation, ubiquitination and caspase 8-mediated cleavage. It interacts with other cellular RHIM-containing adapters to initiate gene activation and cell death (PMID: 15258597) and forms a necrosis-inducing complex with RIPK3 (PMID: 19524513, 19524512). TNFR1 activation by TNF-alpha family cytokines leads to TRADD and TRAF2 recruitment and Lys-63 ubiquitination by TRAF2 acts as a critical enhancer of communication with downstream MAPK and NF-kappa-B signal transducers, which in turn mediate activation of pro-inflammatory genes (PMID: 11101870, 15258597, 17389591, 19524512, 119524513). Disrupted TNF-mediated RIPK1 ubiquitination induces activation of cell death via apoptosis or necroptosis.

Dysfunction and disease

Both mono- and bi-allelic variants in RIPK1 are associated with inborn errors of immunity (IEIs). Dominant pathogenic variants that block Caspase-8-mediated RIPK1 cleavage lead to its over-activation, and the promotion of RDA and necroptosis, associated with CRIA, a predominantly autoinflammatory disease featuring recurrent fevers and intermittent lymphadenopathy (PMID: 31827281, 31827280). Recessive RIPK1 deficiency due to pathogenic LOF variants leads to reduced NF-kB activation and dysregulat ed cell death under specific stimulatory conditions. These patients present with variable immunodeficiency, gastrointestinal (GI) issues, and arthritis (PMID: 30026316, 30591564, 31213653). Rarely, neurodevelopmental issues have been reported in addition to the features described above (PMID: 31213653). Most recently, compound heterozygous missense variants leading to an autosomal recessive gain-of-function mechanism were reported in patients with autoinflammatory features (recurrent fevers, lymphadenopathy and skin rash) driven by RIPK1 activation-induced T cell death (https://doi.org/10.1101/2024.03.28.24304774). [Load More]