Human cytomegalovirus (HCMV) has evolved sophisticated immune evasion mechanismsthat target both the innate and adaptive immune responses. However, how HCMV encodedproteins are involved in this immune escape is not clear. Here, we show that HCMV glycoproteinUS9 inhibits the IFN-B response by targeting the mitochondrial antiviral-signalingprotein (MAVS) and stimulator of interferon genes (STING)-mediated signaling pathways.US9 accumulation in mitochondria attenuates the mitochondrial membrane potential, leadingto promotion of MAVS leakage from the mitochondria. Furthermore, US9 disrupts STINGoligomerization and STING-TBK1 association through competitive interaction. Intriguingly,US9 blocks interferon regulatory factor 3 (IRF3) nuclear translocation and its cytoplasmicdomain is essential for inhibiting IRF3 activation. Mutant HCMV lacking US7-16 is impaired inantagonism of MAVS/STING-mediated IFN-B expression, an effect that is reversible by theintroduction of US9. Our findings indicate that HCMV US9 is an antagonist of IFN signaling topersistently evade host innate antiviral responses.
Bibliographical noteFunding Information:
We thank Dr Jun-Young Seo (Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea) for HCMV AD169, AD169ΔUS7-16, E. coli SW105 strain, pO6-SVT-entry plasmid, and HFF cells. This study was supported by grants from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C2542), and from Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and future planning (2015R1A2A1A15055053 and 2017R1E1A1A01074135). This work was also supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIP) (NRF-2016R1A5A1010764), and by the Strategic Initiative for Microbiomes in Agriculture and Food funded by Ministry of Agriculture, Food and Rural Affairs (916006-2). S.L. was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015R1D1A1A01060181), and a research grant from the National Cancer Center of Korea (NCC-1710210). H.J.C. was supported by NRF (National Research Foundation of Korea) grant funded by the Korean Government (NRF-2013-Global Ph. D. Fellowship Program). H.J.C., A.P., S.K., T.A.L., and E.A.R. were supported by Brain Korea (BK21) PLUS Program.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)