Dataset Information

MAT2A-Mediated S-Adenosylmethionine Level in CD4⁺ T Cells Regulates HIV-1 Latent Infection.

ABSTRACT: Antiretroviral drugs effectively halt HIV-1 replication and disease progression, however, due to the presence of a stable viral latent reservoir, the infection cannot be cured by antiretroviral drugs alone. Elucidating the molecular mechanisms underlying HIV-1 latent infection remains a critical hurdle that precludes the development of novel therapeutic strategies aiming for a potential functional cure. Cellular metabolism has been reported to affect HIV-1 replication in CD4⁺ T cells, but it remains largely unclear whether it is involved in the regulation of HIV-1 latency. Here, we performed a sub-pooled CRISPR library knockout screen targeting 1773 metabolic-related genes in a cell model of HIV-1 latent infection and found that Methionine Adenosyltransferase 2A (MAT2A) contributes to HIV-1 latency. MAT2A knockout enhanced the reactivation of latent HIV-1 while MAT2A overexpression did the opposite. Mechanistically, MAT2A modulates HIV-1 latency through S-Adenosylmethionine (SAM)-mediated one-carbon flux. MAT2A knockout resulted in a significant downregulation of DNA and histone methylation at the HIV-1 5'-LTR. Importantly, we found that the plasma level of SAM is positively correlated with HIV-1 DNA in PBMCs from ART-treated infected individuals, suggesting SAM could serve as a potential biomarker for the latent viral reservoir. Overall, this study reveals an important role of MAT2A-mediated one-carbon metabolism in regulating HIV-1 latency and provides a promising target for the development of new strategies for a functional cure of HIV-1.

SUBMITTER: Yang X

PROVIDER: S-EPMC8488394 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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MAT2A-Mediated S-Adenosylmethionine Level in CD4<sup>+</sup> T Cells Regulates HIV-1 Latent Infection.

Yang Xiaofan X Huang Ting T Wang Tiantian T Gao Hongbo H Zhang Haitao H Peng Wen W Zhao Jiacong J Hu Shujing S Lu Panpan P Hong Zhongsi Z Li Bo B Deng Kai K

Frontiers in immunology 20210920

Antiretroviral drugs effectively halt HIV-1 replication and disease progression, however, due to the presence of a stable viral latent reservoir, the infection cannot be cured by antiretroviral drugs alone. Elucidating the molecular mechanisms underlying HIV-1 latent infection remains a critical hurdle that precludes the development of novel therapeutic strategies aiming for a potential functional cure. Cellular metabolism has been reported to affect HIV-1 replication in CD4<sup>+</sup> T cells, ...[more]

PMID: 34616406

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Project description:BackgroundMyasthenia gravis (MG) is an autoimmune disease characterized by pathogenic antibodies that target structures of the neuromuscular junction. The evidence suggests that the regulation of long noncoding RNAs (lncRNAs) that is mediated by transcription factors (TFs) plays a key role in the pathophysiology of MG. Nevertheless, the detailed molecular mechanisms of lncRNAs in MG remain largely undetermined.MethodsUsing microarray analysis, we analyzed the lncRNA levels in MG. By bioinformatics analysis, LINC01566 was found to potentially play an important role in MG. First, qRT‒PCR was performed to verify the LINC1566 expressions in MG patients. Then, fluorescence in situ hybridization was conducted to determine the localization of LINC01566 in CD4 + T cells. Finally, the impact of LINC01566 knockdown or overexpression on CD4 + T-cell function was also analyzed using flow cytometry and CCK-8 assay. A dual-luciferase reporter assay was used to validate the binding of the TF FOSL1 to the LINC01566 promoter.ResultsBased on the lncRNA microarray and differential expression analyses, we identified 563 differentially expressed (DE) lncRNAs, 450 DE mRNAs and 19 DE TFs in MG. We then constructed a lncRNA-TF-mRNA network. Through network analysis, we found that LINC01566 may play a crucial role in MG by regulating T-cell-related pathways. Further experiments indicated that LINC01566 is expressed at low levels in MG patients. Functionally, LINC01566 is primarily distributed in the nucleus and can facilitate CD4 + T-cell apoptosis and inhibit cell proliferation. Mechanistically, we hypothesized that LINC01566 may negatively regulate the expressions of DUSP3, CCR2, FADD, SIRPB1, LGALS3 and SIRPB1, which are involved in the T-cell activation pathway, to further influence the cellular proliferation and apoptosis in MG. Moreover, we found that the effect of LINC01566 on CD4 + T cells in MG was mediated by the TF FOSL1, and in vitro experiments indicated that FOSL1 can bind to the promoter region of LINC01566.ConclusionsIn summary, our research revealed the protective roles of LINC01566 in clinical samples and cellular experiments, illustrating the potential roles and mechanism by which FOSL1/LINC01566 negatively regulates CD4 + T-cell activation in MG.

Dataset Information

MAT2A-Mediated S-Adenosylmethionine Level in CD4⁺ T Cells Regulates HIV-1 Latent Infection.

Publications

MAT2A-Mediated S-Adenosylmethionine Level in CD4<sup>+</sup> T Cells Regulates HIV-1 Latent Infection.

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Dataset Information

MAT2A-Mediated S-Adenosylmethionine Level in CD4+ T Cells Regulates HIV-1 Latent Infection.

Publications

MAT2A-Mediated S-Adenosylmethionine Level in CD4<sup>+</sup> T Cells Regulates HIV-1 Latent Infection.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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MAT2A-Mediated S-Adenosylmethionine Level in CD4⁺ T Cells Regulates HIV-1 Latent Infection.