Toll-like Receptor-Mediated Downregulation of the Deubiquitinase CYLD Protects Macrophages from Necroptosis in Wild-Derived Mice [Gene Regulation]
April 4th, 2014 by Schworer, S. A., Smirnova, I. I., Kurbatova, I., Bagina, U., Churova, M., Fowler, T., Roy, A. L., Degterev, A., Poltorak, A.
Pathogen recognition by the innate immune system initiates the production of pro-inflammatory cytokines but can also lead to programmed host cell death. Necroptosis, a caspase-independent cell death pathway, can contribute to 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 mechanisms of RIP1-mediated activation of immune cells, we established a genetic screen based on RIP1-mediated necroptosis in wild-derived MOLF mice, which diverged from classical laboratory mice over a million years ago. When compared to C57BL/6, MOLF macrophages were resistant to RIP1-mediated necroptosis induced by TLRs. Using a forward genetic approach in a backcross panel of mice, we identified CYLD, a deubiquitinase known to act directly on RIP1 and promote necroptosis in TNFR signaling, as the gene conferring the trait. We demonstrate that CYLD is required for TLR-induced necroptosis and describe a novel mechanism by which CYLD is downregulated at the transcriptional level in MOLF macrophages to confer protection from necroptosis.