The ER-resident ubiquitin-specific protease 19 participates in the UPR and rescues ERAD substrates.
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.
Hassink
Gerco C
GC
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Zhao
Bin
B
Sompallae
Ramakrishna
R
Altun
Mikael
M
Gastaldello
Stefano
S
Zinin
Nikolay V
NV
Masucci
Maria G
MG
Lindsten
Kristina
K
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
D012333:RNA, Messenger; D010450:Endopeptidases; D064570:Ubiquitin-Specific Proteases