Impaired endocytosis and accumulation in early endosomal compartments defines herpes simplex virus–mediated disruption of the nonclassical MHC class I–related molecule MR1

Samer, Carolyn, McWilliam, Hamish E.G., McSharry, Brian P., Burchfield, James G., Stanton, Richard J. ORCID: https://orcid.org/0000-0002-6799-1182, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Villadangos, Jose A., Abendroth, Allison and Slobedman, Barry 2024. Impaired endocytosis and accumulation in early endosomal compartments defines herpes simplex virus–mediated disruption of the nonclassical MHC class I–related molecule MR1. Journal of Biological Chemistry 300 (10) , 107748. 10.1016/j.jbc.2024.107748

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Abstract

Presentation of metabolites by the major histocompatibility complex class I–related protein 1 (MR1) molecule to mucosal-associated invariant T cells is impaired during herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections. This is surprising given these viruses do not directly synthesise MR1 ligands. We have previously identified several HSV proteins responsible for rapidly downregulating the intracellular pool of immature MR1, effectively inhibiting new surface antigen presentation, while preexisting ligand-bound mature MR1 is unexpectedly upregulated by HSV-1. Using flow cytometry, immunoblotting, and high-throughput fluorescence microscopy, we demonstrate that the endocytosis of surface MR1 is impaired during HSV infection and that internalized molecules accumulate in EEA1-labeled early endosomes, avoiding degradation. We establish that the short MR1 cytoplasmic tail is not required for HSV-1–mediated downregulation of immature molecules; however it may play a role in the retention of mature molecules on the surface and in early endosomes. We also determine that the HSV-1 US3 protein, the shorter US3.5 kinase and the full-length HSV-2 homolog, all predominantly target mature surface rather than total MR1 levels. We propose that the downregulation of intracellular and cell surface MR1 molecules by US3 and other HSV proteins is an immune-evasive countermeasure to minimize the effect of impaired MR1 endocytosis, which might otherwise render infected cells susceptible to MR1-mediated killing by mucosal-associated invariant T cells.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Elsevier
ISSN:	0021-9258
Date of First Compliant Deposit:	28 October 2024
Date of Acceptance:	13 August 2024
Last Modified:	29 Oct 2024 12:00
URI:	https://orca.cardiff.ac.uk/id/eprint/173461

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