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Open AccessArticle

The E3 Ubiquitin Ligase TMEM129 Is a Tri-Spanning Transmembrane Protein

Medical Microbiology, University Medical Center Utrecht, 3584CX Utrecht, The Netherlands
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Authors to whom correspondence should be addressed.
These authors contributed equally to this study.
Academic Editor: Jaquelin Dudley
Viruses 2016, 8(11), 309; https://doi.org/10.3390/v8110309
Received: 9 September 2016 / Revised: 3 November 2016 / Accepted: 4 November 2016 / Published: 15 November 2016
(This article belongs to the Special Issue Viruses, ERAD, and the Proteasome)
Misfolded proteins from the endoplasmic reticulum (ER) are transported back into the cytosol for degradation via the ubiquitin-proteasome system. The human cytomegalovirus protein US11 hijacks this ER-associated protein degradation (ERAD) pathway to downregulate human leukocyte antigen (HLA) class I molecules in virus-infected cells, thereby evading elimination by cytotoxic T-lymphocytes. Recently, we identified the E3 ubiquitin ligase transmembrane protein 129 (TMEM129) as a key player in this process, where interference with TMEM129 activity in human cells completely abrogates US11-mediated class I degradation. Here, we set out to further characterize TMEM129. We show that TMEM129 is a non-glycosylated protein containing a non-cleaved signal anchor sequence. By glycosylation scanning mutagenesis, we show that TMEM129 is a tri-spanning ER-membrane protein that adopts an Nexo–Ccyto orientation. This insertion in the ER membrane positions the C-terminal really interesting new gene (RING) domain of TMEM129 in the cytosol, making it available to catalyze ubiquitination reactions that are required for cytosolic degradation of secretory proteins. View Full-Text
Keywords: ER-associated protein degradation; ERAD; TMEM129; E3 ligase; topology; transmembrane; RING domain ER-associated protein degradation; ERAD; TMEM129; E3 ligase; topology; transmembrane; RING domain
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Van de Weijer, M.L.; Van Muijlwijk, G.H.; Visser, L.J.; Costa, A.I.; Wiertz, E.J.H.J.; Lebbink, R.J. The E3 Ubiquitin Ligase TMEM129 Is a Tri-Spanning Transmembrane Protein. Viruses 2016, 8, 309.

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