PPM1G restricts innate immune signaling mediated by STING and MAVS and is hijacked by KSHV for immune evasion.

The adaptor proteins, STING and MAVS, are components of critical pathogen-sensing pathways that induce innate immunity. Phosphorylation of either adaptor results in activation of the type I interferon pathway. How this phosphorylation is regulated and how it is manipulated by pathogens remain largely unknown. Here, we identified host protein phosphatase, Mg2+/Mn2+ dependent 1G (PPM1G) as a negative regulator of innate immune pathways and showed that this host system is hijacked by Kaposi's sarcoma-associated herpesvirus (KSHV). Mechanistically, KSHV tegument protein ORF33 interacts with STING/MAVS and enhances recruitment of PPM1G to dephosphorylate p-STING/p-MAVS for immunosuppression. Inhibition of PPM1G expression improves the antiviral response against both DNA and RNA viruses. Collectively, our study shows that PPM1G restricts both cytosolic DNA- and RNA-sensing pathways to naturally balance the intensity of the antiviral response. Manipulation of PPM1G by KSHV provides an important strategy for immune evasion.