1. Academic Validation
  2. FKBP12 mediates necroptosis by initiating RIPK1-RIPK3-MLKL signal transduction in response to TNF receptor 1 ligation

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

  • J Cell Sci. 2019 May 20;132(10):jcs227777. doi: 10.1242/jcs.227777.
Zicheng Wang 1 2 3 Jiannan Feng 2 3 Jiyun Yu 1 Guozhu Chen 4
Affiliations

Affiliations

  • 1 Institute of Military Cognition and Brain Sciences, Academy of Military Medical Sciences, Beijing 100850, China.
  • 2 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
  • 3 Beijing Key Laboratory of Therapeutic Gene Engineering Antibody, Beijing 100850, China.
  • 4 Institute of Military Cognition and Brain Sciences, Academy of Military Medical Sciences, Beijing 100850, China chenguozhu2002@126.com.
Abstract

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 (TNF). Although many target proteins for Necroptosis have been identified, no report had indicated that FK506-binding protein 12 (FKBP12, also known as FKBP1A), an endogenous protein that regulates protein folding and conformation alteration, is involved in mediating Necroptosis. In this study, we found that FKBP12 acts as a novel target protein in mediating Necroptosis and the related systemic inflammatory response syndrome triggered by TNF. The mechanistic study discovered that FKBP12 is essential for initiating necrosome formation and RIPK1-RIPK3-MLKL signaling pathway activation in response to TNF 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 could be a potential therapeutic target for the clinical treatment of necroptosis-associated diseases.

Keywords

FK506-binding protein 12; Necroptosis; Receptor-interacting serine/threonine-protein kinase 1; Receptor-interacting serine/threonine-protein kinase 3; Tumor necrosis factor.

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