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Viruses 2016, 8(11), 309;

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

Medical Microbiology, University Medical Center Utrecht, 3584CX Utrecht, The Netherlands
These authors contributed equally to this study.
Authors to whom correspondence should be addressed.
Academic Editor: Jaquelin Dudley
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)
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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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