Open AccessFKBP12 mediates necroptosis by initiating RIPK1/RIPK3/MLKL signal transduction in response to TNF receptor 1 ligation
Author(s) -
Zicheng Wang,
Jie Feng,
Jiyun Yu,
Guozhu Chen
Publication year - 2019
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.227777
Subject(s) - necroptosis , ripk1 , biology , signal transduction , microbiology and biotechnology , phosphorylation , protein kinase a , programmed cell death , kinase , tumor necrosis factor alpha , cancer research , immunology , biochemistry , apoptosis
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.