Antiviral activity of a purine synthesis enzyme reveals a key role of deamidation in regulating protein nuclear import. Sci Adv 2019 Oct;5(10):eaaw7373
Date
10/22/2019Pubmed ID
31633017Pubmed Central ID
PMC6785261DOI
10.1126/sciadv.aaw7373Scopus ID
2-s2.0-85073598592 (requires institutional sign-in at Scopus site) 18 CitationsAbstract
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 diminishing RTA nuclear localization and transcriptional activation. Finally, RTA proteins of all gamma herpesviruses appear to be regulated by PFAS-mediated deamidation. These findings uncover an unexpected function of a metabolic enzyme in restricting viral replication and a key role of deamidation in regulating protein nuclear import.
Author List
Li J, Zhao J, Xu S, Zhang S, Zhang J, Xiao J, Gao R, Tian M, Zeng Y, Lee K, Tarakanova V, Lan K, Feng H, Feng PAuthor
Vera Tarakanova PhD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceAsparagine
Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor
Cell Nucleus
HEK293 Cells
Herpesvirus 8, Human
Humans
Immediate-Early Proteins
Mutagenesis, Site-Directed
Protein Binding
RNA Interference
RNA, Small Interfering
Sequence Alignment
Trans-Activators
Transcriptional Activation
Viral Proteins
beta Karyopherins