biostudies-literatureLi JNational Institute of Allergy and Infectious DiseasesNIDCR NIH HHSNIAID NIH HHSNational Cancer InstituteNational Institute of Dental and Craniofacial ResearchNCI NIH HHSeaaw7373https://www.ebi.ac.uk/biostudies/studies/S-EPMC6785261biostudies-literatureUnknown5(10)Protein nuclear translocation is highly regulated and crucial for diverse biological processes. However, our understanding concerning protein nuclear import is incomplete. Here we report that a cellular purine synthesis enzyme inhibits protein nuclear import via deamidation. Employing human Kaposi's sarcoma-associated herpesvirus (KSHV) to probe the role of protein deamidation, we identified a purine synthesis enzyme, phosphoribosylformylglycinamidine synthetase (PFAS) that inhibits KSHV transcriptional activation. PFAS deamidates the replication transactivator (RTA), a transcription factor crucial for KSHV lytic replication. Mechanistically, deamidation of two asparagines flanking a positively charged nuclear localization signal impaired the binding of RTA to an importin β subunit, thus dScience advancesAntiviral activity of a purine synthesis enzyme reveals a key role of deamidation in regulating protein nuclear import.PMC6785261DE026003DE027556P01 CA180779R03 DE022521R35 DE027557R01 CA203923R35 DE027556AI134105CA221521R01 CA221521R21 AI134105Tarakanova VLi JTian MZhang JLee KZeng YZhang SGao RXiao JFeng HLan KXu SZhao JFeng PfalseAntiviral activity of a purine synthesis enzyme reveals a key role of deamidation in regulating protein nuclear import.Protein nuclear translocation is highly regulated and crucial for diverse biological processes. However, our understanding concerning protein nuclear import is incomplete. Here we report that a cellular purine synthesis enzyme inhibits protein nuclear import via deamidation. Employing human Kaposi's sarcoma-associated herpesvirus (KSHV) to probe the role of protein deamidation, we identified a purine synthesis enzyme, phosphoribosylformylglycinamidine synthetase (PFAS) that inhibits KSHV transcriptional activation. PFAS deamidates the replication transactivator (RTA), a transcription factor crucial for KSHV lytic replication. Mechanistically, deamidation of two asparagines flanking a positively charged nuclear localization signal impaired the binding of RTA to an importin β subunit, thus d2019-01-01T00:00:00Z2019 Oct2025-04-19T17:10:25.709Z2019-10-30T08:19:13ZS-EPMC67852613163301710.1126/sciadv.aaw7373