title: Necrosome core machinery: MLKL.
abstract: In the study of regulated cell death, the rapidly expanding field of regulated necrosis, in particular necroptosis, has been drawing much attention. The signaling of necroptosis represents a sophisticated form of a death pathway. Anti-caspase mechanisms (e.g., using inhibitors of caspases, or genetic ablation of caspase-8) switch cell fate from apoptosis to necroptosis. The initial extracellular death signals regulate RIP1 and RIP3 kinase activation. The RIP3-associated death complex assembly is necessary and sufficient to initiate necroptosis. MLKL was initially identified as an essential mediator of RIP1/RIP3 kinase-initiated necroptosis. Recent studies on the signal transduction using chemical tools and biomarkers support the idea that MLKL is able to make more functional sense for the core machinery of the necroptosis death complex, called the necrosome, to connect to the necroptosis execution. The experimental data available now have pointed that the activated MLKL forms membrane-disrupting pores causing membrane leakage, which extends the prototypical concept of morphological and biochemical events following necroptosis happening in vivo. The key role of MLKL in necroptosis signaling thus sheds light on the logic underlying this unique "membrane-explosive" cell death pathway. In this review, we provide the general concepts and strategies that underlie signal transduction of this form of cell death, and then focus specifically on the role of MLKL in necroptosis.
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Rd, Shanghai, 200031, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Rd, Shanghai, 200031, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Rd, Shanghai, 200031, China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: He
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Rd, Shanghai, 200031, China. liming.sun@sibcb.ac.cn.
authors.forename: Liming
authors.initials: L
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002462:Cell Membrane / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D051379:Mice; D009336:Necrosis / Q000473:pathology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; C570693:MLKL protein, human; D011494:Protein Kinases; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
keywords: MLKL; Necroptosis; Necrosome; Pore-forming protein; Regulated cell death