RIPK1 Gene

CRIA syndrome; autoinflammatory syndrome; 

The RIPK1 gene (RIPK1 stands for "Receptor Interacting Serine/Threonine Kinase 1") is a protein-coding gene located on chromosome 6p25.2.

The RIPK1 gene encodes a member of the so-called RIP (Receptor-Interacting Protein) family of serine/threonine protein kinases. The encoded RIP protein plays a role in inflammation and apoptosis in response to tissue damage, in pathogen recognition, and in developmental regulation. RIPK1/RIPK3 kinase-mediated necrosis is known as necroptosis. Genetic disruption of this gene causes death in mice immediately after birth.

Serine-threonine kinase encoded by the RIPK1 gene is a key regulator of TNF-mediated apoptosis, necroptosis, and inflammatory pathways. Exhibits kinase activity-dependent functions that regulate cell death and kinase-independent scaffold functions that regulate inflammatory signaling and cell survival. The encoded protein also has kinase-independent scaffold functions: upon binding of TNF to TNFR1, RIPK1 is recruited to the TNF-R1 signaling complex (TNF-RSC, also known as complex I), where it functions as a scaffold protein and promotes cell survival, in part by activating the canonical NF-kappa-B pathway (similarity). Kinase activity is critical for the regulation of necroptosis and apoptosis, two parallel forms of cell death: upon activation of its protein kinase activity, it regulates the formation of two complexes leading to apoptosis. These are complex IIa (RIPK1-FADD-CASP8), which drives apoptosis, and complex IIb (RIPK1-RIPK3-MLKL), which drives necroptosis. The RIPK1 gene is required to limit CASP8-dependent TNFR1-induced apoptosis. Under normal conditions, RIPK1 acts as an inhibitor of RIPK3-dependent necroptosis. In addition to apoptosis and necroptosis, it is also involved in the inflammatory response by promoting transcriptional production of pro-inflammatory cytokines such as interleukin-6 (IL6).

Biallelic loss-of-function variants of RIPK1 can cause RIPK1 deficiency, which is associated with immunodeficiency and inflammatory diseases. In contrast, certain heterozygous variants prevent the cleavage of RIPK1 by caspase-8 and lead to the autoinflammatory CRIA syndrome, which is characterized by, among other things, recurrent fever and lymphadenopathy, as well as neutrophilic exanthems (Sweet’s syndrome).

1. Cuchet-Lourenco D et al. (2018) Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science 361: 810-813.
2. Degterev A et al (2019) Targeting RIPK1 for the treatment of human diseases. Proc Natl Acad Sci U S A 116: 9714-9722.
3. Lalaoui N et al (2020) Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature 577(7788):103-108.