Caspase-11 controls interleukin-1β release through degradation of TRPC1

Cell Rep. 2014 Mar 27;6(6):1122-1128. doi: 10.1016/j.celrep.2014.02.015. Epub 2014 Mar 13.

Abstract

Caspase-11 is a highly inducible caspase that controls both inflammatory responses and cell death. Caspase-11 controls interleukin 1β (IL-1β) 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-1β without modulating caspase-1 cleavage or cell death in cultured macrophages. Consistently, trpc1(-/-) mice show higher IL-1β 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspases / metabolism*
  • HEK293 Cells
  • Humans
  • Interleukin-1beta / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • TRPC Cation Channels / deficiency
  • TRPC Cation Channels / metabolism
  • TRPC Cation Channels / physiology*
  • Transfection

Substances

  • Interleukin-1beta
  • TRPC Cation Channels
  • transient receptor potential cation channel, subfamily C, member 1
  • Casp4 protein, mouse
  • Caspases