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Volume 105, Issue 4

HCMV US2 co-opts TRC8 to degrade the endoplasmic reticulum-resident protein LMAN2L Open Access

Abstract

The human cytomegalovirus (HCMV) pUS2 glycoprotein exploits the host’s endoplasmic reticulum (ER)-associated degradation (ERAD) pathway to degrade major histocompatibility complex class I (MHC-I) and prevent antigen presentation. Beyond MHC-I, pUS2 has been shown to target a range of cellular proteins for degradation, preventing their cell surface expression. Here we have identified a novel pUS2 target, ER-resident protein lectin mannose binding 2 like (LMAN2L). pUS2 expression was both necessary and sufficient for the downregulation of LMAN2L, which was dependent on the cellular E3 ligase TRC8. Given the hypothesized role of LMAN2L in the trafficking of glycoproteins, we employed proteomic plasma membrane profiling to measure LMAN2L-dependent changes at the cell surface. A known pUS2 target, integrin alpha-6 (ITGA6), was downregulated from the surface of LMAN2L-deficient cells, but not other integrins. Overall, these results suggest a novel strategy of pUS2-mediated protein degradation whereby pUS2 targets LMAN2L to impair trafficking of ITGA6. Given that pUS2 can directly target other integrins, we propose that this single viral protein may exhibit both direct and indirect mechanisms to downregulate key cell surface molecules.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): cytomegalovirus , plasma membrane , protein degradation , protein trafficking and proteomics
Funding
This study was supported by the:
  • NIHR Cambridge Biomedical Research Centre (Award NIHR203312)
    • Principle Award Recipient: MichaelP. Weekes
  • Wellcome Trust (Award 226615/Z/22/Z)
    • Principle Award Recipient: RichardJ. Stanton
  • Medical Research Council (Award MR/S00971X/1)
    • Principle Award Recipient: RichardJ. Stanton
  • Wellcome Trust (Award 220015/Z/19/Z)
    • Principle Award Recipient: LeahM. Hunter
  • Wellcome Trust (Award 108070/Z/15/Z)
    • Principle Award Recipient: MichaelP. Weekes
© 2024 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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HCMV US2 co-opts TRC8 to degrade the endoplasmic reticulum-resident protein LMAN2L
J. Gen. Virol. 105, 001980 (2024); https://doi.org/10.1099/jgv.0.001980
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