Human cytomegalovirus-encoded US9 targets MAVS and STING signaling to evade type I interferon immune responses

Hyun jin Choi, Areum Park, Sujin Kang, Eunhye Lee, Taeyun A. Lee, Eun A. Ra, Jiseon Lee, Sungwook Lee () and Boyoun Park ()
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Hyun jin Choi: Yonsei University
Areum Park: Yonsei University
Sujin Kang: Yonsei University
Eunhye Lee: Yonsei University
Taeyun A. Lee: Yonsei University
Eun A. Ra: Yonsei University
Jiseon Lee: National Cancer Center
Sungwook Lee: National Cancer Center
Boyoun Park: Yonsei University

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract Human cytomegalovirus (HCMV) has evolved sophisticated immune evasion mechanisms that target both the innate and adaptive immune responses. However, how HCMV encoded proteins are involved in this immune escape is not clear. Here, we show that HCMV glycoprotein US9 inhibits the IFN-β response by targeting the mitochondrial antiviral-signaling protein (MAVS) and stimulator of interferon genes (STING)-mediated signaling pathways. US9 accumulation in mitochondria attenuates the mitochondrial membrane potential, leading to promotion of MAVS leakage from the mitochondria. Furthermore, US9 disrupts STING oligomerization and STING–TBK1 association through competitive interaction. Intriguingly, US9 blocks interferon regulatory factor 3 (IRF3) nuclear translocation and its cytoplasmic domain is essential for inhibiting IRF3 activation. Mutant HCMV lacking US7-16 is impaired in antagonism of MAVS/STING-mediated IFN-β expression, an effect that is reversible by the introduction of US9. Our findings indicate that HCMV US9 is an antagonist of IFN signaling to persistently evade host innate antiviral responses.

Date: 2018
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DOI: 10.1038/s41467-017-02624-8

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