Caspase-11 Controls Interleukin-1β Release through Degradation of TRPC1
Bénédicte F. Py,
Mingzhi Jin,
Bimal N. Desai,
Anirudh Penumaka,
Hong Zhu,
Maike Kober,
Alexander Dietrich,
Marta M. Lipinski,
Thomas Henry,
David E. Clapham,
Junying Yuan
Affiliations
Bénédicte F. Py
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Mingzhi Jin
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Bimal N. Desai
Department of Cardiology, Howard Hughes Medical Institute, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Anirudh Penumaka
Department of Cardiology, Howard Hughes Medical Institute, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Hong Zhu
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Maike Kober
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Alexander Dietrich
Walther Straub Institute of Pharmacology and Toxicology, German Lung Center (DZL), Ludwig Maximilian University Munich, 80336 Munich, Germany
Marta M. Lipinski
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Thomas Henry
International Center for Infectiology Research, INSERM U1111, CNRS UMR5308, École Normale Supérieure de Lyon, Claude Bernard Lyon 1 University, 69007 Lyon, France
David E. Clapham
Department of Cardiology, Howard Hughes Medical Institute, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Junying Yuan
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
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.
