Viral pseudo-enzyme facilitates KSHV lytic replication via suppressing PFAS-mediated RTA deamidation

Abstract

Background Deamidation, a type of post-translational modification commonly considered a hallmark of protein “aging” and function decay, is increasingly recognized for its pivotal role in regulating biological processes and viral infection. Our previous study has demonstrated that the deamidation of replication and transcription activator (RTA), a master regulator of ubiquitous and oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV), mediated by phosphoribosylformylglycinamidine synthetase (PFAS), hinders its nuclear import and transcriptional activity. Results Here we report that the viral glutamine amidotransferase (vGAT) pseudo-enzyme was exploited to promote KSHV lytic infection through inhibition of PFAS-mediated RTA deamidation, RTA nuclear localization, and NF-κB activation. To be more specific, vGAT competitively interacted with RTA and cellular PFAS, thereby suppressing the deamidation and nuclear localization of RTA, while concomitantly augmenting RTA-mediated transcriptional activation. Consistently, the RTA deamidation-resistant mutant demonstrated elevated levels of transcriptional activity and lytic replication. Lastly, vGAT appeared to regulate the deamidation process of multiple viral proteins in KSHV. Conclusions Collectively, these findings unveil that a viral pseudo-enzyme was exploited to enhance viral infection via deamidation regulation.