Journal
CELL REPORTS
Volume 6, Issue 6, Pages 1122-1128Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.02.015
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Funding
- National Institute on Aging [R37 AG012859]
- French National Research Agency [ANR-13-JSV3-0002-01]
- European Research Council [ERC-2012-StG_20111109]
- Agence Nationale de la Recherche (ANR) [ANR-13-JSV3-0002] Funding Source: Agence Nationale de la Recherche (ANR)
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Caspase-11 is a highly inducible caspase that controls both inflammatory responses and cell death. Caspase-11 controls interleukin 1 beta (IL-1 beta) secretion by potentiating caspase-1 activation and induces caspase-1-independent pyroptosis downstream of noncanonical NLRP3 inflammasome activators such as lipopolysaccharide (LPS) and Gram-negative bacteria. However, we still know very little about the downstream mechanism of caspase-11 in regulating inflammation because the known substrates of caspase-11 are only other caspases. Here, we identify the cationic channel subunit transient receptor potential channel 1 (TRPC1) as a substrate of caspase-11. TRPC1 deficiency increases the secretion of IL-1 beta without modulating caspase-1 cleavage or cell death in cultured macrophages. Consistently, trpc1(-/-) mice show higher IL-1 beta secretion in the sepsis model of intraperitoneal LPS injection. Altogether, our data suggest that caspase-11 modulates the cationic channel composition of the cell and thus regulates the unconventional secretion pathway in a manner independent of caspase-1.
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