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Antiviral activity of a purine synthesis enzyme reveals a key role of deamidation in regulating protein nuclear import. Sci Adv 2019 10;5(10):eaaw7373

Date

10/22/2019

Pubmed ID

31633017

Pubmed Central ID

PMC6785261

DOI

10.1126/sciadv.aaw7373

Scopus ID

2-s2.0-85073598592   2 Citations

Abstract

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 P

Author

Vera Tarakanova PhD Associate Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Asparagine
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
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a