Year: 2023
Type: article
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.
Source: Nucleic Acids Research
DOI: 10.1093/nar/gkad941
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,630
Awards: 人源赖氨酰tRNA合成酶LysRS特异的分子探针设计与多酶复合物MSC的调控机制研究, G245506646, Targeting HIV-1 RNA modifications in latently infected CD4+ T cells for therapeutic development, G3370924295, SAMHD1-mediated regulation of HIV-1 innate immunity and viral gene expression, G5571406773, HIV-1-induced upregulation of m6A modifications of cellular RNA in CD4+ T-cells, G7638398202, G9000012471, G9000043682, G9000213050, Center for Structural Biology of HIV RNA
OpenAlex ID: W4388454584