HSV-1 employs UL56 to antagonize expression and function of cGAMP channels

Henry T W Blest; Alexander Redmond; Jed Avissar; Jake Barker; Anne Bridgeman; Gerissa Fowler; Lise Chauveau; Jonny Hertzog; Iolanda Vendrell; Roman Fischer; Marie B Iversen; Lichen Jing; David M Koelle; Søren R Paludan; Benedikt M Kessler; Colin M Crump; Jan Rehwinkel

doi:10.1016/j.celrep.2024.114122

HSV-1 employs UL56 to antagonize expression and function of cGAMP channels

Cell Rep. 2024 Apr 22;43(5):114122. doi: 10.1016/j.celrep.2024.114122. Online ahead of print.

Authors

Henry T W Blest¹, Alexander Redmond¹, Jed Avissar¹, Jake Barker², Anne Bridgeman¹, Gerissa Fowler¹, Lise Chauveau¹, Jonny Hertzog¹, Iolanda Vendrell³, Roman Fischer³, Marie B Iversen⁴, Lichen Jing⁵, David M Koelle⁶, Søren R Paludan⁴, Benedikt M Kessler³, Colin M Crump², Jan Rehwinkel⁷

Affiliations

¹ Medical Research Council Translational Immune Discovery Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS Oxford, UK.
² Department of Pathology, University of Cambridge, CB2 1QP Cambridge, UK.
³ Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁴ Department of Biomedicine, Aarhus University, Aarhus Aarhus C, Denmark.
⁵ Department of Medicine, University of Washington, Seattle, WA 98195, USA.
⁶ Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA; Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Global Health, University of Washington, Seattle, WA 98195, USA; Benaroya Research Institute, Seattle, WA 98101, USA.
⁷ Medical Research Council Translational Immune Discovery Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS Oxford, UK. Electronic address: jan.rehwinkel@imm.ox.ac.uk.

PMID: 38652659
DOI: 10.1016/j.celrep.2024.114122

Abstract

DNA sensing is important for antiviral immunity. The DNA sensor cGAS synthesizes 2'3'-cyclic GMP-AMP (cGAMP), a second messenger that activates STING, which induces innate immunity. cGAMP not only activates STING in the cell where it is produced but cGAMP also transfers to other cells. Transporters, channels, and pores (including SLC19A1, SLC46A2, P2X7, ABCC1, and volume-regulated anion channels (VRACs)) release cGAMP into the extracellular space and/or import cGAMP. We report that infection with multiple human viruses depletes some of these cGAMP conduits. This includes herpes simplex virus 1 (HSV-1) that targets SLC46A2, P2X7, and the VRAC subunits LRRC8A and LRRC8C for degradation. The HSV-1 protein UL56 is necessary and sufficient for these effects that are mediated at least partially by proteasomal turnover. UL56 thereby inhibits cGAMP uptake via VRAC, SLC46A2, and P2X7. Taken together, HSV-1 antagonizes intercellular cGAMP transfer. We propose that this limits innate immunity by reducing cell-to-cell communication via the immunotransmitter cGAMP.

Keywords: CP: Immunology; CP: Microbiology; DNA sensing; LRRC8A; P2X7; SLC46A2; STING; UL56; VRAC; cGAMP; cGAMP transport; herpes simplex virus.