CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN
Autor: | Adrian T. Ting, Emiko Mizoguchi, Jianke Zhang, Diana Legarda, Rosalind L. Ang, Michelle A. Kelliher, Matija Zelic, Nimisha Rikhi, Scott J. Justus, Thomas M. Moran, J. Magarian Blander, Wenjing Li |
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Rok vydání: | 2014 |
Předmět: |
0301 basic medicine
Lipopolysaccharides Necroptosis Apoptosis Mice Transgenic Biology Caspase 8 Models Biological General Biochemistry Genetics and Molecular Biology Article Deubiquitinating Enzyme CYLD 03 medical and health sciences Mice Necrosis medicine Animals Receptors Tumor Necrosis Factor Type II lcsh:QH301-705.5 Tumor Necrosis Factor-alpha Macrophages Cell biology Mice Inbred C57BL Toll-Like Receptor 4 Adaptor Proteins Vesicular Transport Cysteine Endopeptidases 030104 developmental biology lcsh:Biology (General) TRIF Cytoprotection Interferon Type I Proteolysis TLR4 Tumor necrosis factor alpha Signal transduction Protein Kinases Interferon type I medicine.drug Signal Transduction |
Zdroj: | Cell Reports, Vol 15, Iss 11, Pp 2449-2461 (2016) |
ISSN: | 2211-1247 |
Popis: | SummaryTumor necrosis factor (TNF) induces necroptosis, a RIPK3/MLKL-dependent form of inflammatory cell death. In response to infection by Gram-negative bacteria, multiple receptors on macrophages, including TLR4, TNF, and type I IFN receptors, are concurrently activated, but it is unclear how they crosstalk to regulate necroptosis. We report that TLR4 activates CASPASE-8 to cleave and remove the deubiquitinase cylindromatosis (CYLD) in a TRIF- and RIPK1-dependent manner to disable necroptosis in macrophages. Inhibiting CASPASE-8 leads to CYLD-dependent necroptosis caused by the TNF produced in response to TLR4 ligation. While lipopolysaccharides (LPS)-induced necroptosis was abrogated in Tnf−/− macrophages, a soluble TNF antagonist was not able to do so in Tnf+/+ macrophages, indicating that necroptosis occurs in a cell-autonomous manner. Surprisingly, TNF-mediated auto-necroptosis of macrophages requires type I IFN, which primes the expression of key necroptosis-signaling molecules, including TNFR2 and MLKL. Thus, the TNF necroptosis pathway is regulated by both negative and positive crosstalk. |
Databáze: | OpenAIRE |
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