RIPK1 binds STUB1

Stable Identifier
Reaction [binding]
Homo sapiens
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The binding of TNF-α to TNF receptor 1 (TNFR1) results in the sequential formation of several signaling complexes (Walczak H 2011). The rapidly forming complex-I (TNFR1 signaling complex) is assembled at the receptor’s cytoplasmic tail and consists of TNFR1, TRADD (TNFR1-associated death domain), TRAF2 (TNF receptor associated factor-2), RIPK1 (receptor-interacting serine/threonine protein kinase 1), and E3 ubiquitin (Ub) ligases BIRC2, BIRC3 (cIAP1/2, cellular inhibitor of apoptosis) and LUBAC (linear ubiquitin chain assembly complex) (Micheau O and Tschopp J 2003; Yuan J et al. 2019). Within this complex, RIPK1 and other proteins are rapidly conjugated with Ub chains by various E3 ligases (Micheau O and Tschopp J 2003; Yuan J et al. 2019). The ubiquitination status of RIPK1 determines cell fate downstream of the TNFR1 signaling complex (Yuan J et al. 2019). The conjugation of K63-linked Ub chains by BIRC2/3 or Met1-linked Ub chains by LUBAC, have been shown to promote RIPK1-dependent pro-survival NF-kappa-B signaling while inhibiting RIPK1 kinase-mediated apoptosis and necroptosis. In addition, RIPK1 also interacts with FADD/Caspase-8 or RIPK3/MLKL to form complex IIa or IIb, which activate apoptosis or necroptosis respectively (Yuan J et al. 2019). In these cell death-inducing complexes, RIPK1 function is also regulated by ubiquitination (Amin P et al. 2018; de Almagro MC et al. 2015). The protein stability of RIPK1 is negatively regulated by the carboxyl-terminus of HSC70-interacting protein (CHIP, also known as STIP1 homology and U-Box containing protein 1, STUB1) (Seo J et al. 2016). STUB1 (CHIP), as an E3 ligase, mediates K48-linked ubiquitination of RIPK1 at K571, K604, and K627 and targets it to lysosomal degradation (Seo J et al. 2016). Co-immunoprecipitation analysis using overexpressed proteins revealed interactions between STUB1 (CHIP) and RIPK1 in human embryonic kidney 293T (HEK293T) cells (Seo J et al. 2016). Interaction of endogenous STUB1 and RIPK1 proteins was detected in mouse fibroblast L929 cells. Direct interaction between recombinant proteins was confirmed by GST-pull-down assay (Seo J et al. 2016). Domain mapping revealed that the RHIM domain of RIPK1 interacts with the U-Box domain of STUB1 (Seo J et al. 2016). Similarly, STUB1 interacts with and ubiquitinates RIPK3 inducing lysosome-dependent destabilization of RIPK3 (Seo J et al. 2016). These data suggest that the E3 ligase activity of STUB1 negatively regulates TNF-α–induced cell death by conjugating K48-linked ubiquitin chains to RIPK1 and RIPK3, thereby promoting their degradation.

This Reactome event describes STUB1 (CHIP) binding to RIPK1.

Literature References
PubMed ID Title Journal Year
26900751 CHIP controls necroptosis through ubiquitylation- and lysosome-dependent degradation of RIPK3

Shin, J, Sung, H, Seo, J, Seong, D, Song, J, Kim, JH, Dondelinger, Y, Lee, C, Han, SY, Vandenabeele, P, Lee, EW, Lee, HK, Seong, JK, Jeong, M

Nat. Cell Biol. 2016
Orthologous Events
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