Editors' ChoiceImmunology

Membrane Fusion Stimulates STING

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Science Signaling  31 Jul 2012:
Vol. 5, Issue 235, pp. ec202
DOI: 10.1126/scisignal.2003446

The innate immune response to viral infection involves the detection of viral nucleic acids by a range of sensors, including endosomal Toll-like receptors (TLRs), as well as cytosolic RNA helicase RIG-I–like receptors and DNA sensors. TLR signaling depends on the adaptor proteins MyD88 or TRIF, whereas signaling by cytosolic sensors depends on the adaptor protein MAVS or the endoplasmic reticulum (ER)–resident protein STING. Both pathways lead to the expression of interferon (IFN)–stimulated genes (ISGs). Noting that plasma membrane perturbations stimulate type I IFN production (see commentary by Olagnier and Hiscott), Holm et al. investigated mechanisms for the detection of viruses that do not depend on viral nucleic acids. The authors prepared virus-like particles (VLPs) from herpes simplex virus type I (HSV-1) that were deficient in viral capsid protein and DNA. Exposure of mouse dendritic cells or human macrophages to VLPs resulted in the expression of ISGs and production of the chemokine CXCL10. Exposure of cells to VLPs did not induce inflammasome activity or autophagy, which are hallmarks of many viral infections. VLPs generated from mutant strains of HSV-1 that were fusion-deficient failed to induce production of type I IFNs or CXCL10. Experiments with liposomes of various compositions showed that the extent of CXCL10 production increased with increasing fusogenic potential. Exposure of VLPs to peritoneal cells from mice deficient in various receptors or adaptors in HSV-sensing pathways demonstrated that only STING was required for CXCL10 production. STING relocalized from the ER to perinuclear regions in VLP-exposed cells, similar to the effect seen in HSV-infected cells. VLPs stimulated intracellular Ca2+ flux in exposed cells, and inhibitors of phospholipase Cγ or phosphatidylinositol 3-kinase blocked VLP-induced expression of the gene encoding CXCL10. Together, these data suggest that membrane fusion by virus acts as a danger signal to trigger a STING-dependent antiviral response that results in IFN production.

C. K. Holm, S. B. Jensen, M. R. Jakobsen, N. Cheshenko, K. A. Horan, H. B. Moeller, R. Gonzalez-Dosal, S. B. Rasmussen, M. H. Christensen, T. O. Yarovinsky, F. J. Rixon, B. C. Herold, K. A. Fitzgerald, S. R. Paludan, Virus-cell fusion as a trigger of innate immunity dependent on the adaptor STING. Nat. Immunol. 13, 737–743 (2012). [PubMed]

D. Olagnier, J. Hiscott, Breaking the barrier: Membrane fusion triggers innate antiviral immunity. Nat. Immunol. 13, 713–715 (2012). [PubMed]

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