Abstract
Casein kinases are a large family of intracellular serine/threonine kinases that control a variety of cellular signaling functions. Here we report that a member of casein kinase 1 family, casein kinase 1G2, CSNK1G2, binds and inhibits the activation of receptor-interacting kinase 3, RIPK3, thereby attenuating RIPK3-mediated necroptosis. The binding of CSNK1G2 to RIPK3 is triggered by auto-phosphorylation at serine 211/threonine 215 sites in its C-terminal domain. CSNK1G2-knockout mice showed significantly enhanced necroptosis response and premature aging of their testis, a phenotype that was rescued by either double knockout of the Ripk3 gene or feeding the animal with a RIPK1 kinase inhibitor-containing diet. Moreover, CSNK1G2 is also co-expressed with RIPK3 in human testis, and the necroptosis activation marker phospho-MLKL was observed in the testis of old (>80) but not young men, indicating that the testis-aging program carried out by the RIPK3-mediated and CSNK1G2-attenuated necroptosis is evolutionarily conserved between mice and men.
Highlights
RIP3 is an intracellular serine/threonine kinase with key roles in necroptosis, a regulated form of necrotic cell death, and activation of inflammasome for the release of inflammatory cytokines (Christofferson and Yuan, 2010; Vandenabeele et al., 2010; Wallach et al, 2016)
Necroptosis is actively suppressed by caspase-8-mediated cleavage of RIP1 and RIP3, whose upstream activation pathway is often shared between caspase-8 and RIP1 kinase
Embryonic lethality in caspase-8 knockout mice is rescued by double knockout RIP3 or MLKL; and cellular necroptosis induction by TNF-α or TLRs are dramatically enhanced if caspase-8 activity is suppressed (Dannappel et al, 2014; Dillon et al, 2014; Gunther et al, 2011; He et al, 2009; Kaiser et al, 2011; Newton et al, 2019; Oberst et al, 2011; Rickard et al, 2014; Takahashi et al, 2014)
Summary
RIP3 is an intracellular serine/threonine kinase with key roles in necroptosis, a regulated form of necrotic cell death, and activation of inflammasome for the release of inflammatory cytokines (Christofferson and Yuan, 2010; Vandenabeele et al., 2010; Wallach et al, 2016). In response of TNF-family of cytokines, Toll-like receptors, and Z-RNAs, RIP3 is activated either by a related kinase RIP1, or adaptor proteins TRIF, or ZBP1/DAI, respectively (Cho et al, 2009; Degterev et al, 2008; He et al, 2009; Zhang et al, 2009; Zhang et al, 2020). Knocking out CSNK1G2, in mouse or multiple cell lines including cell lines derived from spermatocyte and Sertoli cells significantly enhanced necroptosis response and the CSNK1G2 knockout mice showed pre-maturing aging of their testis. CSNK1G2 is a major negative regulator of necroptosis via prevention of RIP3 activation
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