Cell Rep. 2014 Mar 27;6(6):1122-8. doi: 10.1016/j.celrep.2014.02.015. Epub 2014 Mar 13.

Caspase-11 controls interleukin-1beta release through degradation of TRPC1.External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c

Py, B. F., Jin, M., Desai, B. N., Penumaka, A., Zhu, H., Kober, M., Dietrich, A., Lipinski, M. M., Henry, T., Clapham, D. E., Yuan, J.,
["Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; International Center for Infectiology Research, INSERM U1111, CNRS UMR5308, Ecole Normale Superieure de Lyon, Claude Bernard Lyon 1 University, 69007 Lyon, France.", "Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.", "Department of Cardiology, Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.", "Department of Cardiology, Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.", "Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.", "Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.", "Walther Straub Institute of Pharmacology and Toxicology, German Lung Center (DZL), Ludwig Maximilian University Munich, 80336 Munich, Germany.", "Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.", "International Center for Infectiology Research, INSERM U1111, CNRS UMR5308, Ecole Normale Superieure de Lyon, Claude Bernard Lyon 1 University, 69007 Lyon, France.", "Department of Cardiology, Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.", "Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: junying_yuan@hms.harvard.edu."]
Caspase-11 is a highly inducible caspase that controls both inflammatory responses and cell death. Caspase-11 controls interleukin 1beta (IL-1beta) 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-1beta without modulating caspase-1 cleavage or cell death in cultured macrophages. Consistently, trpc1(-/-) mice show higher IL-1beta 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.
PMID: 24630989External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c
Screening Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Experimental screening Non-experimental screening Reference
TRP channel construct Interactor source
TRP channel Interactor Method Species Region Species Organ/tissue Sample type
TRPC1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 Caspase-1 Speculation Prediction 24630989
TRPC1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 Caspase-4/Caspase-11 Yeast two-hybrid Not specified Not specified 24630989
TRPC2 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 Caspase-4/Caspase-11 Speculation Prediction 24630989
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
Validation: In vitro validation Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Assay with recombinant proteins Reference
TRP channel construct Interactor construct
TRP channel Interactor Method Species Region Expression system Species Region Expression system
TRPC1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 Caspase-4/Caspase-11 Fusion protein-pull down assay Not specified Full-length In vitro translation Not specified p30 domain E. coli 24630989
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
Validation: In vivo validation Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Assay with endogenous proteins Assay with overexpressed proteins Reference
Cell or tissue Cell or tissue TRP channel construct Interactor construct
TRP channel Interactor Method Species Region Species Region
TRPC1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 Caspase-1 Co-immunoprecipitation HEK293T Not specified Full-length Not specified Full-length 24630989
TRPC1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 Caspase-4/Caspase-11 Co-immunoprecipitation HEK293T Not specified Full-length Not specified Full-length 24630989
TRPC2 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 Caspase-4/Caspase-11 Co-immunoprecipitation HEK293T Not specified Full-length Not specified Full-length 24630989
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
Characterization Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Binding region mapping Stoichiometry Affinity (Kd) Reference
TRP channel Interactor
TRP channel Interactor Method Species Region Species Region
TRPC1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 Caspase-4/Caspase-11 Co-immunoprecipitation Not specified 1-318 Not specified p30 domain 24630989
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
TRP / Interactor

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