title: Activation of cell-surface proteases promotes necroptosis, inflammation and cell migration.
abstract: Necroptosis is a programmed, caspase-independent cell death that is morphologically similar to necrosis. TNF-induced necroptosis is mediated by receptor-interacting protein kinases, RIP1 and RIP3, and the mixed lineage kinase domain-like (MLKL). After being phosphorylated by RIP3, MLKL is translocated to the plasma membrane and mediates necroptosis. However, the execution of necroptosis and its role in inflammation and other cellular responses remain largely elusive. In this study, we report that MLKL-mediated activation of cell-surface proteases of the a disintegrin and metalloprotease (ADAM) family promotes necroptosis, inflammation and cell migration. ADAMs are specifically activated at the early stage of necroptosis when MLKL is phosphorylated and translocated to the cell plasma membrane. Activation of ADAMs induces ectodomain shedding of diverse cell-surface proteins including adhesion molecules, receptors, growth factors and cytokines. Importantly, the shedding of cell-surface proteins disrupts cell adhesion and accelerates necroptosis, while the soluble fragments of the cleaved proteins trigger the inflammatory responses. We also demonstrate that the shedding of E-cadherin ectodomain from necroptotic cells promotes cell migration. Thus, our study provides a novel mechanism of necroptosis-induced inflammation and new insights into the physiological and pathological functions of this unique form of cell death.
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Anling
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Swati
authors.initials: S
authors.lastname: Choksi
authors.affiliation: Institute of Basic Medical Sciences, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.affiliation: Institute of Basic Medical Sciences, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Institute of Basic Medical Sciences, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China.
authors.forename: Xue-Min
authors.initials: XM
authors.lastname: Zhang
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Zheng-Gang
authors.initials: ZG
authors.lastname: Liu
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology*; D002465:Cell Movement; D004789:Enzyme Activation; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008810:Mice, Inbred C57BL; D009336:Necrosis; D009361:Neoplasm Invasiveness; D010447:Peptide Hydrolases / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism
chemical_list: D015820:Cadherins; C570693:MLKL protein, human; D011494:Protein Kinases; D010447:Peptide Hydrolases; D051722:ADAM Proteins