Abstract
COP9 plays a role in plant innate immunity. The role of COP9 in mammalian innate immune responses is unknown. Here, we show that the COP9 signalosome subunit 5 (CSN5) is required for activation of proinflammatory kinases p38 and Erk and for down-regulation of the expression of genes regulated by nuclear factor E2-related factor 2. Mice with myeloid-specific CSN5 deficiency have lower mortality in polymicrobial sepsis. CSN5 is required for both Toll-like receptor (TLR) and reactive oxygen species-mediated deneddylation of Cul3, which is essential for Cul3/Keap1-mediated degradation of nuclear factor E2-related factor 2. On the basis of our results COP9 subunit CSN5 is considered to be an essential component of mammalian innate immunity.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antioxidants / metabolism
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COP9 Signalosome Complex
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Cullin Proteins / metabolism
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Female
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Immunity, Innate*
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Intracellular Signaling Peptides and Proteins / deficiency
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / immunology*
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Lung / immunology
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Lung / metabolism
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Lung / pathology
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MAP Kinase Signaling System
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Macrophage Activation
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Macrophages / immunology*
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Macrophages / metabolism
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Male
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Mice
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Mice, Knockout
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NF-E2-Related Factor 2 / metabolism
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Peptide Hydrolases / deficiency
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Peptide Hydrolases / genetics
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Peptide Hydrolases / immunology*
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Shock, Septic / immunology
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Shock, Septic / metabolism
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Signal Transduction
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Toll-Like Receptors / metabolism
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Up-Regulation
Substances
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Antioxidants
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Cul3 protein, mouse
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Cullin Proteins
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Intracellular Signaling Peptides and Proteins
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NF-E2-Related Factor 2
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Nfe2l2 protein, mouse
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Toll-Like Receptors
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Peptide Hydrolases
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Cops5 protein, mouse
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COP9 Signalosome Complex