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

Journal article

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.

Authors: Blest, HTW; Redmond, A; Avissar, J; Barker, J; Bridgeman, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Cell Reports
• Volume: 43
• Issue: 5
• Article number: 114122
• Place of publication: United States
• Publication date: 2024-04-22
• Acceptance date: 2024-04-01
• DOI: 10.1016/j.celrep.2024.114122
• EISSN: 2211-1247
• ISSN: 2211-1247
• Pmid: 38652659
• Language: English
• Keywords: LRRC8A; UL56; DNA sensing; SLC46A2; cGAMP; VRAC; P2X7; STING; cGAMP transport; herpes simplex virus