FKBP12 mediates necroptosis by initiating RIPK1–RIPK3–MLKL signal transduction in response to TNF receptor 1 ligation

Necroptosis is a regulated form of necrotic cell death that is mediated by receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like protein (MLKL), which mediates necroptotic signal transduction induced by tumor necrosis factor alpha (TNFα). Although many target proteins for necroptosis have been identified, no report indicates that FK506-binding protein 12 (FKBP12), an endogenous protein that regulates protein folding and conformation alteration, was involved in mediating necroptosis. In this study, we found that FKBP12 acted as a novel target protein in mediating necroptosis and the related systemic inflammatory response syndrome triggered by TNFα. The mechanistic study discovered that FKBP12 is essential for initiating necrosome formation and RIPK1/RIPK3/MLKL signaling pathway activation in response to TNFα receptor 1 ligation. In addition, FKBP12 is indispensable for RIPK1 and RIPK3 expression and subsequent spontaneous phosphorylation, which are essential processes for initial necrosome formation and necroptotic signal transduction; therefore, FKBP12 may target RIPK1 and RIPK3 to mediate necroptosis in vitro and in vivo. Collectively, our data demonstrate that FKBP12 may be a potential therapeutic target for the clinical treatment of necroptosis-associated diseases.