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Py, Benedicte F.; Jin, Mingzhi; Desai, Bimal N.; Penumaka, Anirudh; Zhu, Hong; Kober, Maike; Dietrich, Alexander; Lipinski, Marta M.; Henry, Thomas; Clapham, David E.; Yuan, Junying (2014): Caspase-11 Controls Interleukin-1 beta Release through Degradation of TRPC1. In: Cell Reports, Vol. 6, No. 6: pp. 1122-1128
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Abstract

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.