The cytosolic DNA sensor cGAS recognizes viral DNA and synthesizes the second messenger cGAMP upon viral infection. Human cytomegalovirus (HCMV), a member of the betaherpesvirus family, is a typical dsDNA virus that encodes over 200 proteins. Similar to many other DNA viruses, HCMV infection induces activation of the cGAS-MITA signaling pathway.

Recently, it has been demonstrated that HCMV tegument protein UL82 contributes to HCMV immune evasion by inhibiting the cellular trafficking and activation of MITA/STING to evade antiviral immunity. However, whether the DNA sensor cGAS is targeted by HCMV proteins is largely unclear.

In a recent report, the research group led by Prof. WANG Yanyi in Wuhan Institute of Virology (WIV) of the Chinese Academy of Sciences (CAS), by cooperation with Prof. SHU Hongbing in Wuhan University and Prof. LUO Minhua in WIV, CAS, has identifed HCMV protein UL31 as an inhibitor of cGAS. UL31 interacts with cGAS, disassociates DNA from cGAS, and inhibits production of cGAMP, resulting in impaired antiviral immune responses.

In this study, the cytosolic DNA sensor cGAS recognizes viral DNA and synthesizes the second messenger cGAMP upon viral infection. cGAMP binds to the adaptor protein MITA/STING to activate downstream signaling events, leading to induction of type I interferons (IFNs) and antiviral effector genes. The scientists identify the human cytomegalovirus (HCMV) protein UL31 as an inhibitor of cGAS. UL31 interacts directly with cGAS and disassociates DNA from cGAS, thus inhibiting cGAS enzymatic functions and reducing cGAMP production. UL31 overexpression markedly reduces antiviral responses stimulated by cytosolic DNA, while knockdown or knockout of UL31 heightens HCMV-triggered induction of type I IFNs and downstream antiviral genes. Moreover, wild-type HCMV replicates more efficiently than UL31-deficient HCMV, a phenotype that is reversed in cGAS null cells.

These results highlight the importance of cGAS in the host response to HCMV as well as an important viral strategy to evade this innate immune sensor.

The results have been published in Cell Host & Microbe entitled "Human Cytomegalovirus Protein UL31 Inhibits DNA Sensing of cGAS to Mediate Immune Evasion".

This work was supported by the National Science Fund for Distinguished Young Scholars, the National Natural Science Foundation of China, the Ministry of Science and Technology of China, and the Key Research Programs of Frontier Sciences funded by the Chinese Academy of Sciences.