Binding of TNFα to TNF receptor 1 (TNFR1) induces the sequential formation of several signaling complexes, namely complex I and complex IIa/b (Walczak H 2011; Yuan J et al. 2019). These complexes support either cell survival (complex I) or cell death (complex II). The assembly of these complexes is tightly regulated by proteolysis, ubiquitination and phosphorylation of receptor-interacting serine/threonine protein kinase 1 (RIPK1) and other components of the TNFα signaling pathway (reviewed in Yuan J et al. 2019; Varfolomeev E & Vucic D 2022). RIPK1 functions as a key regulator of both cell survival and cell death (reviewed in Ju E et al. 2022). Enzymatically inactive polyubiquitin-bound RIPK1 serves as a scaffold in the TNFR1 signaling complex (complex I) to recruit TAK1 kinase complex and I-kappa-B kinase (IKK) complex contributing to activation of mitogen-activated protein kinase (MAPK) and NF-kappa-B signaling pathways, which regulate expression of pro-survival and inflammatory genes. Deubiquitination of RIPK1 leads to the activation of RIPK1 kinase activity, which promotes RIPK1 kinase-dependent cell death (reviewed in Ju E et al. 2022). Several deubiquitinating enzymes, such as tumor necrosis factor alpha-induced protein 3 (TNFAIP3, known as Zn finger protein A20) or ubiquitin (Ub) carboxyl-terminal hydrolase CYLD, have been implicated in the regulation of RIPK1 activity. CYLD disassembles both Met1- and Lys63-polyUb chains (Fiil BK et al. 2013; Harhaj EW and Dixit VM 2012; Hrdinka M et al. 2016; Sato Y 2022). Upon TNFα stimulation, CYLD is recruited to the TNFR1 signaling complex along with the linear ubiquitin chain assembly complex (LUBAC). Interaction of CYLD with LUBAC is facilitated by spermatogenesis-associated protein 2 (SPATA2) (Elliott PR et al. 2016; Kupka S et al. 2016; Schlicher L et al. 2016; Wagner SA et al. 2016). The CYLD:SPATA2:LUBAC complex is rapidly recruited into the TNFR1 signaling complex to regulate ubiquitination/deubiquitination downstream of TNFR1 (Wagner SA et al. 2016; Elliott PR et al. 2016; Kupka S et al. 2016; Schlicher L et al. 2016; Wei R et al. 2017; reviewed in Schlicher L et al. 2017).

This Reactome event describes CYLD-mediated cleavage of K63-linked polyubiquitin chains on RIPK1 within the TNFR1 signaling complex. The deubiquitinase activity of CYLD attenuates TNFα-induced NF-kappa-B and MAPK signaling, but promotes cell death.