title: Caspase-11 controls interleukin-1β release through degradation of TRPC1.
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.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; International Center for Infectiology Research, INSERM U1111, CNRS UMR5308, École Normale Supérieure de Lyon, Claude Bernard Lyon 1 University, 69007 Lyon, France.
authors.forename: Bénédicte F
authors.initials: BF
authors.lastname: Py
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mingzhi
authors.initials: M
authors.lastname: Jin
authors.affiliation: Department of Cardiology, Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Bimal N
authors.initials: BN
authors.lastname: Desai
authors.affiliation: Department of Cardiology, Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Anirudh
authors.initials: A
authors.lastname: Penumaka
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Maike
authors.initials: M
authors.lastname: Kober
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, German Lung Center (DZL), Ludwig Maximilian University Munich, 80336 Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dietrich
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Marta M
authors.initials: MM
authors.lastname: Lipinski
authors.affiliation: International Center for Infectiology Research, INSERM U1111, CNRS UMR5308, École Normale Supérieure de Lyon, Claude Bernard Lyon 1 University, 69007 Lyon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Henry
authors.affiliation: Department of Cardiology, Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Clapham
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: junying_yuan@hms.harvard.edu.
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism*; D053471:Caspases, Initiator; D057809:HEK293 Cells; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050052:TRPC Cation Channels / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D014162:Transfection
chemical_list: D053583:Interleukin-1beta; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator