title: The ER-resident ubiquitin-specific protease 19 participates in the UPR and rescues ERAD substrates.
abstract: Ubiquitination regulates membrane events such as endocytosis, membrane trafficking and endoplasmic-reticulum-associated degradation (ERAD). Although the involvement of membrane-associated ubiquitin-conjugating enzymes and ligases in these processes is well documented, their regulation by ubiquitin deconjugases is less well understood. By screening a database of human deubiquitinating enzymes (DUBs), we have identified a putative transmembrane domain in ubiquitin-specific protease (USP)19. We show that USP19 is a tail-anchored ubiquitin-specific protease localized to the ER and is a target of the unfolded protein response. USP19 rescues the ERAD substrates cystic fibrosis transmembrane conductance regulator (CFTR)DeltaF508 and T-cell receptor-alpha (TCRalpha) from proteasomal degradation. A catalytically inactive USP19 was still able to partly rescue TCRalpha but not CFTRDeltaF508, suggesting that USP19 might also exert a non-catalytic function on specific ERAD substrates. Thus, USP19 is the first example of a membrane-anchored DUB involved in the turnover of ERAD substrates.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gerco C
authors.initials: GC
authors.lastname: Hassink
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Sompallae
authors.forename: Mikael
authors.initials: M
authors.lastname: Altun
authors.forename: Stefano
authors.initials: S
authors.lastname: Gastaldello
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Zinin
authors.forename: Maria G
authors.initials: MG
authors.lastname: Masucci
authors.forename: Kristina
authors.initials: K
authors.lastname: Lindsten
mesh_terms: D002462:Cell Membrane / Q000201:enzymology; D010450:Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D064570:Ubiquitin-Specific Proteases
chemical_list: D012333:RNA, Messenger; D010450:Endopeptidases; D064570:Ubiquitin-Specific Proteases