Abstract
ATG16L1 is an essential component of the autophagasome. The T300A allele of ATG16L1 is associated with the increased susceptibility to Crohn disease. In this study, we identified a novel function of ATG16L1, which suppresses signaling of the pro-inflammatory cytokine IL-1β. Deletion of ATG16L1 in mouse embryonic fibroblasts significantly amplifies IL-1β signal transduction cascades. This amplification is due to elevated p62 levels in ATG16L1-deficient cells. We found that ATG16L1 regulates p62 levels via both autolysosomal and proteasomal pathways. For proteasomal degradation, we found that Cullin-3 (Cul-3) is a E3 ubiquitin ligase of p62 and that ATG16L1 is essential for neddylation of Cul-3, a step required for Cul-3 activation. Taken together our data indicate that loss-of-function of ATG16L1 results in a hyper-responsiveness to the IL-1β signaling because of the increased p62 level.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Autophagy / physiology*
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Autophagy-Related Proteins
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cells, Cultured
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Cullin Proteins / genetics
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Cullin Proteins / metabolism
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Embryo, Mammalian / cytology
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Embryo, Mammalian / metabolism*
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Enzyme Activation / physiology
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Fibroblasts / cytology
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Fibroblasts / metabolism*
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Gene Deletion
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism*
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism*
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Mice
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Mice, Knockout
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism
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Sequestosome-1 Protein
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Signal Transduction / physiology*
Substances
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Adaptor Proteins, Signal Transducing
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Atg16l1 protein, mouse
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Autophagy-Related Proteins
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Carrier Proteins
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Cul3 protein, mouse
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Cullin Proteins
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Heat-Shock Proteins
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Interleukin-1beta
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Sequestosome-1 Protein
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Sqstm1 protein, mouse
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Proteasome Endopeptidase Complex