Immunology
Toll-like Receptor-mediated Down-regulation of the Deubiquitinase Cylindromatosis (CYLD) Protects Macrophages from Necroptosis in Wild-derived Mice*

https://doi.org/10.1074/jbc.M114.547547Get rights and content
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Pathogen recognition by the innate immune system initiates the production of proinflammatory cytokines but can also lead to programmed host cell death. Necroptosis, a caspase-independent cell death pathway, can contribute to the host defense against pathogens or cause damage to host tissues. Receptor-interacting protein (RIP1) is a serine/threonine kinase that integrates inflammatory and necroptotic responses. To investigate the mechanisms of RIP1-mediated activation of immune cells, we established a genetic screen on the basis of RIP1-mediated necroptosis in wild-derived MOLF/EiJ mice, which diverged from classical laboratory mice over a million years ago. When compared with C57BL/6, MOLF/EiJ macrophages were resistant to RIP1-mediated necroptosis induced by Toll-like receptors. Using a forward genetic approach in a backcross panel of mice, we identified cylindromatosis (CYLD), a deubiquitinase known to act directly on RIP1 and promote necroptosis in TNF receptor signaling, as the gene conferring the trait. We demonstrate that CYLD is required for Toll-like receptor-induced necroptosis and describe a novel mechanism by which CYLD is down-regulated at the transcriptional level in MOLF/EiJ macrophages to confer protection from necroptosis.

Deubiquitination
Gene Regulation
Mouse Genetics
Necrosis (Necrotic Death)
Toll-like Receptor (TLR)
Forward Genetic Mapping
Wild-derived Mice

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*

This work was supported, in whole or in part, by National Institutes of Health Grants AI056234 and AI090419 (to A. P.). This work was also supported by Government of the Russian Federation (Article 220) Grants GK 11.G34.31.0052, and RFFI 13-04-40267-H13 (to A. P.), by the Eshe Fund, and by the Keck Foundation.

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A. Roy, Tufts University School of Medicine, personal communication.