title: CSN-associated USP48 confers stability to nuclear NF-κB/RelA by trimming K48-linked Ub-chains.
abstract: Diligent balance of nuclear factor kappa B (NF-κB) activity is essential owing to NF-κB's decisive role in cellular processes including inflammation, immunity and cell survival. Ubiquitin/proteasome-system (UPS)-dependent degradation of activated NF-κB/RelA involves the cullin-RING-ubiquitin-ligase (CRL) ECS(SOCS1). The COP9 signalosome (CSN) controls ubiquitin (Ub) ligation by CRLs through the removal of the CRL-activating Ub-like modifier NEDD8 from their cullin subunits and through deubiquitinase (DUB) activity of associated DUBs. However, knowledge about DUBs involved in the regulation of NF-κB activity within the nucleus is scarce. In this study we observed that USP48, a DUB of hitherto ill-defined function identified through a siRNA screen, associates with the CSN and RelA in the nucleus. We show that USP48 trims rather than completely disassembles long K48-linked free and substrate-anchored Ub-chains, a catalytic property only shared with ataxin-3 (Atx3) and otubain-1 (OTU1), and that USP48 Ub-chain-trimming activity is regulated by casein-kinase-2 (CK2)-mediated phosphorylation in response to cytokine-stimulation. Functionally, we demonstrate for the first time the CSN and USP48 to cooperatively stabilize the nuclear pool of RelA, thereby facilitating timely induction and shutoff of NF-κB target genes. In summary, this study demonstrates that USP48, a nuclear DUB regulated by CK2, controls the UPS-dependent turnover of activated NF-κB/RelA in the nucleus together with the CSN. Thereby USP48 contributes to a timely control of immune responses.
authors.affiliation: Otto von Guericke University, Medical Faculty, Institute of Experimental Internal Medicine, 39120 Magdeburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schweitzer
authors.affiliation: Otto von Guericke University, Medical Faculty, Institute of Experimental Internal Medicine, 39120 Magdeburg, Germany. Electronic address: Naumann@med.ovgu.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Naumann
mesh_terms: D055162:Biocatalysis / Q000187:drug effects; D000075686:COP9 Signalosome Complex; D047390:Casein Kinase II / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D016384:Consensus Sequence; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D046912:Multiprotein Complexes; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D047390:Casein Kinase II; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex; C579215:USP48 protein, human; D064570:Ubiquitin-Specific Proteases; D008239:Lysine
keywords: CK2; COP9 signalosome; Deubiquitinase; NF-κB; Nuclear protein turnover; RelA