Toll-like receptor-mediated down-regulation of the deubiquitinase cylindromatosis (CYLD) protects macrophages from necroptosis in wild-derived mice.
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.
From the Graduate Program in Immunology, Medical Scientist Training Program.
Stephen A
SA
Schworer
Department of Integrative Physiology and Pathobiology.
Irina I
II
Smirnova
the Institute of Biology of the Karelian Research Centre, Russian Academy of Sciences, Petrozavodsk, Republic of Karelia 185910, Russia, and.
Irina
I
Kurbatova
the Petrozavodsk State University, Petrozavodsk, Republic of Karelia 185910, Russia.
Uliana
U
Bagina
the Institute of Biology of the Karelian Research Centre, Russian Academy of Sciences, Petrozavodsk, Republic of Karelia 185910, Russia, and.
Maria
M
Churova
Department of Developmental, Molecular, and Chemical Biology, and.
Trent
T
Fowler
From the Graduate Program in Immunology, Department of Developmental, Molecular, and Chemical Biology, and Graduate Program in Genetics, Tufts University School of Medicine, Sackler School of Biomedical Sciences, Tufts University, Boston, Massachusetts 02111.
Ananda L
AL
Roy
Department of Developmental, Molecular, and Chemical Biology, and.
Alexei
A
Degterev
From the Graduate Program in Immunology, the Institute of Biology of the Karelian Research Centre, Russian Academy of Sciences, Petrozavodsk, Republic of Karelia 185910, Russia, and Graduate Program in Genetics, Tufts University School of Medicine, Sackler School of Biomedical Sciences, Tufts University, Boston, Massachusetts 02111, alexander.poltorak@tufts.edu.
Alexander
A
Poltorak
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D003546:Cysteine Endopeptidases / Q000235:genetics*; D000074749:Deubiquitinating Enzyme CYLD; D015536:Down-Regulation; D057809:HEK293 Cells; D006801:Humans; D017737:Macrophages, Peritoneal / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D009336:Necrosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*
D012333:RNA, Messenger; D051193:Toll-Like Receptors; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases
Deubiquitination; Forward Genetic Mapping; Gene Regulation; Mouse Genetics; Necrosis (Necrotic Death); Toll-like Receptor (TLR); Wild-derived Mice