Interferon-independent STING signaling promotes resistance to HSV-1 in vivo

Lívia H Yamashiro; Stephen C Wilson; Huntly M Morrison; Vasiliki Karalis; Jing-Yi J Chung; Katherine J Chen; Helen S Bateup; Moriah L Szpara; Angus Y Lee; Jeffery S Cox; Russell E Vance

doi:10.1038/s41467-020-17156-x

Interferon-independent STING signaling promotes resistance to HSV-1 in vivo

Nat Commun. 2020 Jul 7;11(1):3382. doi: 10.1038/s41467-020-17156-x.

Authors

Lívia H Yamashiro^{1

2}, Stephen C Wilson^{1

3}, Huntly M Morrison¹, Vasiliki Karalis⁴, Jing-Yi J Chung¹, Katherine J Chen¹, Helen S Bateup^{4

5

6}, Moriah L Szpara⁷, Angus Y Lee⁸, Jeffery S Cox^{1

9}, Russell E Vance^{10

11

12

13}

Affiliations

¹ Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA, 94720, USA.
² Howard Hughes Medical Institute, University of California, Berkeley, CA, 94720, USA.
³ Bristol Myers Squibb, 200 Cambridge Park Dr, Cambridge, MA, 02140, USA.
⁴ Division of Neurobiology, Department of Molecular and Cell Biology, University of California, Berkeley, CA, 94720, USA.
⁵ Helen Wills Neuroscience Institute, University of California, Berkeley, CA, 94720, USA.
⁶ Chan Zuckerberg Biohub, San Francisco, CA, 94158, USA.
⁷ Departments of Biology and Biochemistry & Molecular Biology, Center for Infectious Disease Dynamics, Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, Pennsylvania, PA, 16801, USA.
⁸ Cancer Research Laboratory, University of California, Berkeley, CA, 94720, USA.
⁹ Henry Wheeler Center for Emerging and Neglected Diseases, University of California, Berkeley, CA, 94720, USA.
¹⁰ Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA, 94720, USA. rvance@berkeley.edu.
¹¹ Howard Hughes Medical Institute, University of California, Berkeley, CA, 94720, USA. rvance@berkeley.edu.
¹² Cancer Research Laboratory, University of California, Berkeley, CA, 94720, USA. rvance@berkeley.edu.
¹³ Henry Wheeler Center for Emerging and Neglected Diseases, University of California, Berkeley, CA, 94720, USA. rvance@berkeley.edu.

Abstract

The Stimulator of Interferon Genes (STING) pathway initiates potent immune responses upon recognition of DNA. To initiate signaling, serine 365 (S365) in the C-terminal tail (CTT) of STING is phosphorylated, leading to induction of type I interferons (IFNs). Additionally, evolutionary conserved responses such as autophagy also occur downstream of STING, but their relative importance during in vivo infections remains unclear. Here we report that mice harboring a serine 365-to-alanine (S365A) mutation in STING are unexpectedly resistant to Herpes Simplex Virus (HSV)-1, despite lacking STING-induced type I IFN responses. By contrast, resistance to HSV-1 is abolished in mice lacking the STING CTT, suggesting that the STING CTT initiates protective responses against HSV-1, independently of type I IFNs. Interestingly, we find that STING-induced autophagy is a CTT- and TBK1-dependent but IRF3-independent process that is conserved in the STING S365A mice. Thus, interferon-independent functions of STING mediate STING-dependent antiviral responses in vivo.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy
Female
Herpes Simplex / immunology*
Herpesvirus 1, Human
Immune Evasion
Interferon Regulatory Factor-3 / immunology*
Interferon Type I / immunology*
Macrophages / immunology
Male
Membrane Proteins / genetics*
Membrane Proteins / immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Mutant Strains
Point Mutation
Signal Transduction

Substances

Interferon Regulatory Factor-3
Interferon Type I
Irf3 protein, mouse
Membrane Proteins
Sting1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding