Abstract
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.
Highlights
Necroptosis is a regulated signaling pathway leading to necrotic cell death
Because TRIF-dependent necroptosis is activated via an intrinsic mechanism, whereas activation of MyD88-dependent necroptosis requires TNF receptor 1 (TNFR1), these data suggest that autocrine production of TNF is necessary for MyD88-dependent, but not for TRIF-dependent, TLR-mediated necroptosis, as described recently using TNFdeficient macrophages [27]
Genome-wide ChIP sequencing data in primary murine B cells confirms that this region is subject to similar regulation in other cell types.3. These results strongly suggest that a difference in transcription at the Cyld locus associated with a loss of RNA polymerase II (Pol II) pausing may be the underlying reason for the acute down-regulation in CYLD following TLR stimulation in MOLF macrophages, leading to less CYLD deubiquitinase activity on RIP1
Summary
Results: Genetic mapping identified that down-regulation of the deubiquitinase CYLD confers resistance to necroptosis in a wild-derived mouse strain. Significance: Genetic diversity of wild-derived mice underlies phenotypic diversity, which can identify novel mechanisms of regulation in cell death signaling. 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
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