Caspase-8-mediated cleavage inhibits IRF-3 protein by facilitating its proteasome-mediated degradation

Nathaniel Sears; Ganes C Sen; George R Stark; Saurabh Chattopadhyay

doi:10.1074/jbc.M111.257022

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Caspase-8-mediated cleavage inhibits IRF-3 protein by facilitating its proteasome-mediated degradation

Journal article

Open access

Peer reviewed

Caspase-8-mediated cleavage inhibits IRF-3 protein by facilitating its proteasome-mediated degradation

Nathaniel Sears, Ganes C Sen, George R Stark and Saurabh Chattopadhyay

The Journal of biological chemistry, Vol.286(38), pp.33037-33044

09/23/2011

DOI: 10.1074/jbc.M111.257022

PMCID: PMC3190878

PMID: 21816816

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Abstract

Interferon regulatory factor 3 (IRF-3) plays a central role in inducing the expression of cellular antiviral genes, including the interferon-β gene, in response to Pattern Recognition Receptors. IRF-3 is targeted for proteasome-mediated degradation, which modulates the strength and duration of the innate immune responses that depend on it. We have found that caspase-8, which is activated by cytosolic RIG-I-dependent signaling, catalyzes an essential intermediate step in the ubiquitination and proteasome-mediated degradation of IRF-3. Mutation of a consensus cleavage site within IRF-3 generates a form that is not cleaved by caspase-8 and that is protected from ubiquitination and degradation. An in vitro assay confirms the direct action of caspase-8 cleavage on IRF-3. We also show that caspase-8-mediated cleavage of IRF-3 helps to modulate dsRNA-dependent gene induction.

RNA Helicases - metabolism

Signal Transduction

Humans

Caspase 8 - metabolism

Gene Expression Regulation

Mutant Proteins - metabolism

Mutation - genetics

Sendai virus - metabolism

Ubiquitination

Models, Biological

Cell Line, Tumor

Interferon Regulatory Factor-3 - metabolism

Protein Processing, Post-Translational

RNA, Double-Stranded - metabolism

Enzyme Activation

Proteasome Endopeptidase Complex - metabolism

Details

Title: Subtitle: Caspase-8-mediated cleavage inhibits IRF-3 protein by facilitating its proteasome-mediated degradation
Creators: Nathaniel Sears - Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
Ganes C Sen
George R Stark
Saurabh Chattopadhyay
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.286(38), pp.33037-33044
DOI: 10.1074/jbc.M111.257022
PMID: 21816816
PMCID: PMC3190878
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: P01 CA062220 / NCI NIH HHS R01 CA095851 / NCI NIH HHS R01 AI073303 / NIAID NIH HHS P01 CA 062220 / NCI NIH HHS
Language: English
Date published: 09/23/2011
Academic Unit: Ophthalmology and Visual Sciences
Record Identifier: 9983980078702771

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