Reactome | ULK1 phosphorylates RIPK1 at S357

ULK1 phosphorylates RIPK1 at S357

Stable Identifier

R-HSA-9819106

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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Autophagy controls programmed cell death through different cross-talk signals (Bray K et al. 2012; Goodall ML et al. 2016; Lim J et al 2019; Wu W et al. 2020). For instance, serine/threonine kinase Unc-51-like kinase-1 (ULK1), an essential initiator of the autophagy response, regulates the tumor necrosis factor α (TNFα)-induced signaling pathway (Wu W et al. 2020; reviewed in Zou L et al. 2022). TNFα binds TNF receptor 1 (TNFR1) inducing the sequential formation of several signaling complexes, namely complex I and complex IIa/b (Micheau O and Tschopp J 2003; Walczak H 2011; Yuan J et al. 2019). These complexes support either cell survival (complex I) or cell death (complex II). Receptor-interacting serine/threonine protein kinase 1 (RIPK1) functions as a key regulator of the TNF:TNFR1 signaling pathway (reviewed in Ju E et al. 2022). The RIPK1 activity is tightly regulated by proteolysis, ubiquitination and phosphorylation (reviewed in Delanghe T et al. 2020; Ju E et al. 2022). RIPK1 was identified as a substrate of ULK1 (Wu W et al. 2020). ULK1 deficiency enhanced autophosphorylation of RIPK1 at S166 and association of RIPK1 with FADD in TNF-stimulated mouse fibroblast L929 and MEF cells (Wu W et al. 2020). Co-immunoprecipitation assay showed that ULK1 associated with RIPK1 upon co-expression of tagged proteins in human embryonic kidney 293 (HEK293) cells (Wu W et al. 2020). The interaction between endogenous ULK1 and RIPK1 was detected in TNF-stimulated L929 cells. The kinase activity of ULK1 was found to phosphorylate RIPK1 at S357 in HEK293 (Wu W et al. 2020). The ULK1-mediated phosphorylation of RIPK1 occurred preferentially in the cytosol preventing the formation of complex II (Wu W et al. 2020). These data suggest that ULK1 exerts a cytoprotective function by suppressing RIPK1-mediated cell death.

This Reactome event describes ULK1-mediated phosphorylation of RIPK1 at S357 within the cytosolic TRAF2:TRADD:RIPK1 complex.

Literature References

PubMed ID	Title	Journal	Year
32320653	The Autophagy-Initiating Kinase ULK1 Controls RIPK1-Mediated Cell Death Wu, W, Wang, X, Berleth, N, Deitersen, J, Wallot-Hieke, N, Böhler, P, Schlütermann, D, Stuhldreier, F, Cox, J, Schmitz, K, Seggewiß, S, Peter, C, Kasof, G, Stefanski, A, Stühler, K, Tschapek, A, Gödecke, A, Stork, B	Cell Rep	2020