FOXO1 promotes HIV latency by suppressing ER stress in T cells
- 15 June 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Microbiology
- Vol. 5 (9), 1144-1157
- https://doi.org/10.1038/s41564-020-0742-9
Abstract
Quiescence is a hallmark of CD4+ T cells latently infected with human immunodeficiency virus 1 (HIV-1). While reversing this quiescence is an effective approach to reactivate latent HIV from T cells in culture, it can cause deleterious cytokine dysregulation in patients. As a key regulator of T-cell quiescence, FOXO1 promotes latency and suppresses productive HIV infection. We report that, in resting T cells, FOXO1 inhibition impaired autophagy and induced endoplasmic reticulum (ER) stress, thereby activating two associated transcription factors: activating transcription factor 4 (ATF4) and nuclear factor of activated T cells (NFAT). Both factors associate with HIV chromatin and are necessary for HIV reactivation. Indeed, inhibition of protein kinase R-like ER kinase, an ER stress sensor that can mediate the induction of ATF4, and calcineurin, a calcium-dependent regulator of NFAT, synergistically suppressed HIV reactivation induced by FOXO1 inhibition. Thus, our studies uncover a link of FOXO1, ER stress and HIV infection that could be therapeutically exploited to selectively reverse T-cell quiescence and reduce the size of the latent viral reservoir.Keywords
This publication has 83 references indexed in Scilit:
- ER stress potentiates insulin resistance through PERK-mediated FOXO phosphorylationGenes & Development, 2013
- FoxO1 Protein Cooperates with ATF4 Protein in Osteoblasts to Control Glucose HomeostasisOnline Journal of Public Health Informatics, 2012
- ATF4-dependent transcription mediates signaling of amino acid limitationTrends in Endocrinology & Metabolism, 2009
- Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in miceJCI Insight, 2009
- Synergistic Activation of HIV-1 Expression by Deacetylase Inhibitors and Prostratin: Implications for Treatment of Latent InfectionPLOS ONE, 2009
- West Nile Virus Infection Activates the Unfolded Protein Response, Leading to CHOP Induction and ApoptosisJournal of Virology, 2007
- Signal integration in the endoplasmic reticulum unfolded protein responseNature Reviews Molecular Cell Biology, 2007
- Gene expression profiling identifies FKBP39 as an inhibitor of autophagy in larval Drosophila fat bodyCell Death & Differentiation, 2007
- Targeting homeostatic mechanisms of endoplasmic reticulum stress to increase susceptibility of cancer cells to fenretinide-induced apoptosis: the role of stress proteins ERdj5 and ERp57British Journal of Cancer, 2007
- Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cellsProceedings of the National Academy of Sciences of the United States of America, 2004