title: The subunit CSN6 of the COP9 signalosome is cleaved during apoptosis.
abstract: The COP9 signalosome is a large multiprotein complex that consists of eight subunits termed CSN1-CSN8. The diverse functions of the COP9 complex include regulation of several important intracellular pathways, including the ubiquitin/proteasome system, DNA repair, cell cycle, developmental changes, and some aspects of immune responses. Nod1 is also thought to be an important cytoplasmic receptor involved in innate immune responses. It detects specific motifs of bacterial peptidoglycan, and this results in activation of multiple signaling pathways and changes in cell function. In this report, we performed a yeast two-hybrid screening and discovered that Nod1 interacts with several components of the COP9 signalosome through its CARD domain. Moreover, we observed that activation of the Nod1 apoptotic pathway leads to specific cleavage of the subunit CSN6. This cleavage is concomitant with caspase processing and generates a short amino-terminal peptide of 3 kDa. A complete inhibition of this cleavage was achieved in the presence of the broad spectrum pharmacological inhibitor of apoptosis, Z-VAD. Furthermore, overexpression of CLARP, a specific caspase 8 inhibitor, completely blocked cleavage of CSN6. Taken together, these results suggest a critical role of caspase 8 in the processing of CSN6. Moreover, these findings suggest that CSN6 cleavage may result in modifications of functions of the COP9 complex that are involved in apoptosis.
authors.affiliation: Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: da Silva Correia
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Miranda
authors.forename: Nikki
authors.initials: N
authors.lastname: Leonard
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ulevitch
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D000075686:COP9 Signalosome Complex; D053181:Caspase 8 / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D004260:DNA Repair / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D046912:Multiprotein Complexes / Q000378:metabolism*; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D046912:Multiprotein Complexes; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D009842:Oligopeptides; D021122:Protein Subunits; D025801:Ubiquitin; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex; D053181:Caspase 8; D046988:Proteasome Endopeptidase Complex