Sester, Martina, Ruszics, Zsolt , Mackley, Emma and Burgert, Hans-Gerhard (2013) The transmembrane domain of the adenovirus E3/19K protein acts as an ER retention signal and contributes to intracellular sequestration of MHC class I molecules. Journal of Virology, Volume 87 (Number 11). pp. 6101-6117. ISSN 0022-538X.
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Abstract
The human adenovirus E3/19K-protein is a type-I transmembrane glycoprotein of the endoplasmic reticulum (ER) that abrogates cell-surface transport of MHC class-I (MHC-I) and MICA/B-molecules. Previous data suggested that E3/19K comprises two functional modules: a luminal domain for interaction with MHC-I and MICA/B-molecules, and a di-lysine motif in the cytoplasmic tail that confers retrieval from the Golgi back to the ER. This study was prompted by the unexpected phenotype of an E3/19K-molecule that was largely retained intracellularly despite having a mutated ER-retrieval motif. To identify additional structural determinants responsible for ER-localization, chimeric molecules were generated containing the luminal E3/19K-domain and the cytoplasmic and/or transmembrane domain (TMD) of the cell-surface protein MHC-I Kd. These were analysed for transport, cell-surface expression and impact on MHC-I/MICA/B down-regulation. Similar to the retrieval mutant, replacing the cytoplasmic tail of E3/19K allowed only limited transport of the chimera to the cell surface. Efficient cell-surface expression was only achieved by additionally replacing the TMD of E3/19K with that of MHC-I, suggesting that the E3/19K-TMD may confer static ER-retention. This was verified by ER-retention of an MHC-I Kd molecule with the TMD replaced by that of E3/19K. Thus, we have identified the E3/19K TMD as a novel functional element that mediates static ER-retention, thereby increasing its ER-concentration. Remarkably, the ER-retrieval signal alone without E3/19K-TMD did not mediate efficient HLA-down regulation, even in the context of infection. This suggests that the TMD is required together with the ER-retrieval function to ensure efficient ER-localization and transport inhibition of MHC-I and MIC-A/B-molecules.
| Item Type: | Journal Article |
|---|---|
| Alternative Title: | The transmembrane domain of the adenovirus E3/19K protein acts as an endoplasmic reticulum retention signal and contributes to intracellular sequestration of major histocompatibility complex class I molecules |
| Subjects: | Q Science > QR Microbiology > QR355 Virology |
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) |
| Library of Congress Subject Headings (LCSH): | Adenoviruses, Major histocompatibility complex, Endoplasmic reticulum, Sequestration (Chemistry) |
| Journal or Publication Title: | Journal of Virology |
| Publisher: | American Society for Microbiology |
| ISSN: | 0022-538X |
| Official Date: | June 2013 |
| Dates: | Date Event June 2013 Published |
| Volume: | Volume 87 |
| Number: | Number 11 |
| Page Range: | pp. 6101-6117 |
| Status: | Peer Reviewed |
| Publication Status: | Published |
| Access rights to Published version: | Open Access (Creative Commons open licence) |
| Date of first compliant deposit: | 19 April 2016 |
| Date of first compliant Open Access: | 19 April 2016 |
| Related URLs: | |
| URI: | https://wrap.warwick.ac.uk/53927/ |
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