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.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)