Multi-targeted loss of the antigen presentation molecule MR1 during HSV-1 and HSV-2 infection

• Published in: iScience 2024-02, Vol.27 (2), p.108801-108801, Article 108801
• Main Authors: Samer, Carolyn, McWilliam, Hamish E.G., McSharry, Brian P., Velusamy, Thilaga, Burchfield, James G., Stanton, Richard J., Tscharke, David C., Rossjohn, Jamie, Villadangos, Jose A., Abendroth, Allison, Slobedman, Barry
• Format: Article
• Language: English
• Subjects: Cell biology; Immunology; Virology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.108801

The major histocompatibility complex (MHC), Class-I-related (MR1) molecule presents microbiome-synthesized metabolites to Mucosal-associated invariant T (MAIT) cells, present at sites of herpes simplex virus (HSV) infection. During HSV type 1 (HSV-1) infection there is a profound and rapid loss of MR1, in part due to expression of unique short 3 protein. Here we show that virion host shutoff RNase protein downregulates MR1 protein, through loss of MR1 transcripts. Furthermore, a third viral protein, infected cell protein 22, also downregulates MR1, but not classical MHC-I molecules. This occurs early in the MR1 trafficking pathway through proteasomal degradation. Finally, HSV-2 infection results in the loss of MR1 transcripts, and intracellular and surface MR1 protein, comparable to that seen during HSV-1 infection. Thus HSV coordinates a multifaceted attack on the MR1 antigen presentation pathway, potentially protecting infected cells from MAIT cell T cell receptor-mediated detection at sites of primary infection and reactivation. [Display omitted] •HSV-1 virion host shutoff (vhs) RNase protein degrades MR1 transcripts•HSV-1 ICP22 protein targets MR1 for proteasomal degradation•HSV-2 downregulation of MR1 transcripts and protein mirrors HSV-1 modulation Cell biology; Immunology; Virology