title: The COP9 signalosome interacts with and regulates interferon regulatory factor 5 protein stability.
abstract: The transcription factor interferon regulatory factor 5 (IRF5) exerts crucial functions in the regulation of host immunity against extracellular pathogens, DNA damage-induced apoptosis, death receptor signaling, and macrophage polarization. Tight regulation of IRF5 is thus warranted for an efficient response toward extracellular stressors and for limiting autoimmune and inflammatory responses. Here we report that the COP9 signalosome (CSN), a general modulator of diverse cellular and developmental processes, associates constitutively with IRF5 and promotes its protein stability. The constitutive CSN/IRF5 interaction was identified using proteomics and confirmed by endogenous immunoprecipitations. The CSN/IRF5 interaction occurred on the carboxyl and amino termini of IRF5; a single internal deletion from amino acids 455 to 466 (Δ455-466) was found to significantly reduce IRF5 protein stability. CSN subunit 3 (CSN3) was identified as a direct interacting partner of IRF5, and knockdown of this subunit with small interfering RNAs resulted in enhanced degradation. Degradation was further augmented by knockdown of CSN1 and CSN3 together. The ubiquitin E1 inhibitor UBEI-41 or the proteasome inhibitor MG132 prevented IRF5 degradation, supporting the idea that its stability is regulated by the ubiquitin-proteasome system. Importantly, activation of IRF5 by the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resulted in enhanced degradation via loss of the CSN/IRF5 interaction. This study defines CSN to be a new interacting partner of IRF5 that controls its stability.
authors.affiliation: Department of Biochemistry & Molecular Biology, New Jersey Medical School, New Jersey Medical School-University Hospital CancerCenter, UMDNJ, Newark, New Jersey, USA.
authors.forename: Justyna
authors.initials: J
authors.lastname: Korczeniewska
authors.forename: Betsy J
authors.initials: BJ
authors.lastname: Barnes
mesh_terms: D000075686:COP9 Signalosome Complex; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D007976:Leupeptins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D021122:Protein Subunits; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D025801:Ubiquitin; D011494:Protein Kinases; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde