Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS
Significance In addition to the well characterized main nuclear latency associated nuclear antigen (LANA) protein of Kaposi sarcoma herpesvirus (KSHV) cytoplasmic LANA isoforms are known to exist, but their function has thus far been unknown. Here we show that N terminally truncated cytoplasmic isoforms of LANA play a role in antagonizing the innate response triggered, by means of cGMP AMP synthase (cGAS) and stimulator of interferon genes (STING) during the reactivation of KSHV from latency. By directly interacting with cGAS, cytoplasmic LANA variants inhibit the cGAS STING dependent induction of interferon and thereby promote the reactivation of KSHV from latency. These findings extend the roles of a g herpesvirus latent protein into the lytic replication cycle. The latency associated nuclear antigen (LANA) of Kaposi sarcoma herpesvirus (KSHV) is mainly localized and functions in the nucleus of latently infected cells, playing a pivotal role in the replication and maintenance of latent viral episomal DNA. In addition, N terminally truncated cytoplasmic isoforms of LANA, resulting from internal translation initiation, have been reported, but their function is unknown. Using coimmunoprecipitation and MS, we found the cGMP AMP synthase (cGAS) an innate immune DNA sensor, to be a cellular interaction partner of cytoplasmic LANA isoforms. By directly binding to cGAS, LANA, and particularly, a cytoplasmic isoform, inhibit the cGAS STING dependent phosphorylation of TBK1 and IRF3 and thereby antagonize the cGAS mediated restriction of KSHV lytic replication. We hypothesize that cytoplasmic forms of LANA, whose expression increases during lytic replication, inhibit cGAS to promote the reactivation of the KSHV from latency. This observation points to a novel function of the cytoplasmic isoforms of LANA during lytic replication and extends the function of LANA from its role during latency to the lytic replication cycle.
Proceedings of the National Academy of Sciences