Journal
EMBO REPORTS
Volume 10, Issue 7, Pages 755-761Publisher
WILEY
DOI: 10.1038/embor.2009.69
Keywords
deubiquitinating enzyme; ubiquitin-specific protease 19; endoplasmic reticulum; ER-associated degradation; unfolded protein response
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Funding
- Swedish Cancer Society
- Swedish Medical Research Council
- Karolinska Institutet
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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) Delta F508 and T-cell receptor-alpha (TCR alpha) from proteasomal degradation. A catalytically inactive USP19 was still able to partly rescue TCR alpha but not CFTR Delta F508, 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.
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