1. Gliotoxin, identified from a screen of fungal metabolites, disrupts 7SK snRNP, releases P-TEFb, and reverses HIV-1 latency
- Author
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Anton Škríba, Abdullah M. S. Al-Hatmi, Annelies Verbon, Vladimír Havlíček, Tokameh Mahmoudi, Elisa De Crignis, Mohammad Javad Najafzadeh, Raquel Crespo, Tsung Wai Kan, Renata Ptackova, Robert-Jan Palstra, Miroslav Sulc, Enrico Ne, Joyce Kang, Michael Roling, Casper Rokx, Elizabeth LeMasters, Peter D. Katsikis, Wilfred F. J. van IJcken, Joyce H.G. Lebbink, Sybren de Hoog, Pritha Biswas, Mateusz Stoszko, Yvonne M. Mueller, Alessia Bertoldi, Biochemistry, Immunology, Radiotherapy, Molecular Genetics, Internal Medicine, Medical Microbiology & Infectious Diseases, and Cell biology
- Subjects
RNA polymerase II ,HIV Infections ,environment and public health ,03 medical and health sciences ,chemistry.chemical_compound ,All institutes and research themes of the Radboud University Medical Center ,Gliotoxin ,SDG 3 - Good Health and Well-being ,Transcription (biology) ,7SK RNA ,Virology ,Gene expression ,Humans ,snRNP ,Positive Transcriptional Elongation Factor B ,P-TEFb ,Molecular Biology ,Research Articles ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,biology ,030306 microbiology ,SciAdv r-articles ,RNA-Binding Proteins ,Ribonucleoproteins, Small Nuclear ,Molecular biology ,3. Good health ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,chemistry ,Ribonucleoproteins ,biology.protein ,HIV-1 ,Small nuclear ribonucleoprotein ,Research Article ,HeLa Cells ,Transcription Factors - Abstract
Gliotoxin, identified from a screen of fungal metabolites, disrupts 7SK snRNP, releases P-TEFb, and reverses HIV-1 latency., A leading pharmacological strategy toward HIV cure requires “shock” or activation of HIV gene expression in latently infected cells with latency reversal agents (LRAs) followed by their subsequent clearance. In a screen for novel LRAs, we used fungal secondary metabolites as a source of bioactive molecules. Using orthogonal mass spectrometry (MS) coupled to latency reversal bioassays, we identified gliotoxin (GTX) as a novel LRA. GTX significantly induced HIV-1 gene expression in latent ex vivo infected primary cells and in CD4+ T cells from all aviremic HIV-1+ participants. RNA sequencing identified 7SK RNA, the scaffold of the positive transcription elongation factor b (P-TEFb) inhibitory 7SK small nuclear ribonucleoprotein (snRNP) complex, to be significantly reduced upon GTX treatment of CD4+ T cells. GTX directly disrupted 7SK snRNP by targeting La-related protein 7 (LARP7), releasing active P-TEFb, which phosphorylated RNA polymerase II (Pol II) C-terminal domain (CTD), inducing HIV transcription.
- Published
- 2019