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. Author manuscript; available in PMC: 2022 Jan 1.
Published in final edited form as: Semin Cell Dev Biol. 2020 Jun 29;109:70–75. doi: 10.1016/j.semcdb.2020.06.013

Figure 3. Cleavage and interaction with other RHIM adaptors prevent inadvertent RIPK1 activation.

Figure 3.

(a) Caspase 8 (Casp8) cleaves RIPK1 at D324. Heterozygous mutations at this cleavage site causes a spontaneous inflammatory disease in human. The non-cleavable RIPK1 unleashes Caspase 8 and RIPK3, which in turn stimulate cell death and elevated inflammatory cytokine production. The red stars represent mutation in D324. KD: kinase domain, R: RHIM, DD: death domain. (b) Genetic evidence indicates that RIPK1 sequesters ZBP1 and/or RIPK3 via the RHIM during perinatal development. This functional interaction is also critical for prevention of cell death and inflammation, and maintenance of homeostasis of the skin epithelium. When the RHIM of RIPK1 is disrupted by genetic manipulation, excessive ZBP1-RIPK3-mediated necroptosis occurs, leading to inflammation and lethality. Zα: zDNA-binding domain.