UMMS Affiliation
Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network
Publication Date
2016-06-14
Document Type
Article
Disciplines
Cancer Biology | Cell Biology
Abstract
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.
DOI of Published Version
10.1016/j.celrep.2016.05.032
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 site
Journal/Book/Conference Title
Cell reports
Related Resources
PubMed ID
27264187
Repository Citation
Legarda D, Justus SJ, Ang RL, Rikhi N, Li W, Moran TM, Zhang J, Mizoguchi E, Zelic M, Kelliher MA, Blander JM, Ting AT. (2016). CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN. Open Access Publications by UMMS Authors. https://doi.org/10.1016/j.celrep.2016.05.032. Retrieved from https://escholarship.umassmed.edu/oapubs/2807
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.