Human lysyl-tRNA synthetase phosphorylation promotes HIV-1 proviral DNA transcription

Author:

Tang Yingke123,Behrens Ryan T4,St Gelais Corine235,Wu Siqi6,Vivekanandan Saravanan7,Razin Ehud8ORCID,Fang Pengfei6ORCID,Wu Li9,Sherer Nathan4ORCID,Musier-Forsyth Karin123ORCID

Affiliation:

1. Department of Chemistry and Biochemistry, Ohio State University , Columbus, OH, USA

2. Center for Retrovirus Research, Ohio State University , Columbus, OH, USA

3. Center for RNA Biology, Ohio State University , Columbus, OH, USA

4. McArdle Laboratory for Cancer Research, Institute for Molecular Virology, & Carbone Cancer Center, University of Wisconsin , Madison , WI, USA

5. Department of Veterinary Biosciences, Ohio State University , Columbus, OH, USA

6. State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences , China

7. Cellular and Molecular Mechanisms of Inflammation Program, National University of Singapore and The Hebrew University of Jerusalem (NUS–HUJ), Singapore

8. Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem , Israel

9. Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa , Iowa City , IA, USA

Abstract

Abstract Human lysyl-tRNA synthetase (LysRS) was previously shown to be re-localized from its normal cytoplasmic location in a multi-aminoacyl-tRNA synthetase complex (MSC) to the nucleus of HIV-1 infected cells. Nuclear localization depends on S207 phosphorylation but the nuclear function of pS207-LysRS in the HIV-1 lifecycle is unknown. Here, we show that HIV-1 replication was severely reduced in a S207A-LysRS knock-in cell line generated by CRISPR/Cas9; this effect was rescued by S207D-LysRS. LysRS phosphorylation up-regulated HIV-1 transcription, as did direct transfection of Ap4A, an upstream transcription factor 2 (USF2) activator that is synthesized by pS207-LysRS. Overexpressing an MSC-derived peptide known to stabilize LysRS MSC binding inhibited HIV-1 replication. Transcription of HIV-1 proviral DNA and other USF2 target genes was reduced in peptide-expressing cells. We propose that nuclear pS207-LysRS generates Ap4A, leading to activation of HIV-1 transcription. Our results suggest a new role for nuclear LysRS in facilitating HIV-1 replication and new avenues for antiviral therapy.

Funder

National Institutes of Health

Israel Science Foundation

National Natural Science Foundation of China

Publisher

Oxford University Press (OUP)

Subject

Genetics

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