CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN
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Authors
Legarda, DianaJustus, Scott J.
Ang, Rosalind L.
Rikhi, Nimisha
Li, Wenjing
Moran, Thomas M.
Zhang, Jianke
Mizoguchi, Emiko
Zelic, Matija
Kelliher, Michelle A.
Blander, J. Magarian
Ting, Adrian T.
Document Type
Journal ArticlePublication Date
2016-06-14
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Tumor 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.Source
Cell Rep. 2016 Jun 14;15(11):2449-61. doi: 10.1016/j.celrep.2016.05.032. Epub 2016 Jun 2. Link to article on publisher's siteDOI
10.1016/j.celrep.2016.05.032Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39998PubMed ID
27264187Related Resources
Link to Article in PubMedDistribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1016/j.celrep.2016.05.032
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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/