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TSC1 and DEPDC5 regulate HIV-1 latency through the mTOR signaling pathway.

Identifieur interne : 000475 ( Main/Exploration ); précédent : 000474; suivant : 000476

TSC1 and DEPDC5 regulate HIV-1 latency through the mTOR signaling pathway.

Auteurs : Shan Jin [République populaire de Chine] ; Qibin Liao [République populaire de Chine] ; Jian Chen [République populaire de Chine] ; Linxia Zhang [République populaire de Chine] ; Qian He [République populaire de Chine] ; Huanzhang Zhu [République populaire de Chine] ; Xiaoyan Zhang [République populaire de Chine] ; Jianqing Xu [République populaire de Chine]

Source :

RBID : pubmed:30087333

Descripteurs français

English descriptors

Abstract

The latent reservoir of HIV-1 presents a major barrier to viral eradication. The mechanism of the establishment and maintenance of the latent viral reservoir is not yet fully understood, which hinders the development of effective curative strategies. In this study, we identified two inhibitory genes, TSC1 and DEPDC5, that maintained HIV-1 latency by suppressing the mTORC1 pathway. We first adapted a genome-wide CRISPR screening approach to identify host factors required for HIV latency in a T-cell-based latency model and discovered two inhibitory genes, TSC1 and DEPDC5, which are potentially involved in HIV-1 latency. Knockout of either TSC1 or DEPDC5 led to enhanced HIV-1 reactivation in both a T-cell line (C11) and a monocyte cell line (U1), and this enhancement could be antagonized by the mTORC1 inhibitor rapamycin. Further evaluation of the mechanism revealed that TSC1 suppresses AKT-mTORC1-S6 via downregulation of Rheb, whereas DEPDC5 inhibits AKT-mTORC1-S6 through RagA. Overall, both TSC1 and DEPDC5 negatively regulate the AKT-mTORC1 pathway, and thus their agonists could be used in the development of new therapeutic approaches for activating HIV-1 latency.

DOI: 10.1038/s41426-018-0139-5
PubMed: 30087333
PubMed Central: PMC6081400


Affiliations:


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<term>Cell Line (MeSH)</term>
<term>HIV Infections (enzymology)</term>
<term>HIV Infections (genetics)</term>
<term>HIV Infections (metabolism)</term>
<term>HIV Infections (virology)</term>
<term>HIV-1 (genetics)</term>
<term>HIV-1 (physiology)</term>
<term>Host-Pathogen Interactions (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (genetics)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (metabolism)</term>
<term>Monomeric GTP-Binding Proteins (genetics)</term>
<term>Monomeric GTP-Binding Proteins (metabolism)</term>
<term>Proto-Oncogene Proteins c-akt (genetics)</term>
<term>Proto-Oncogene Proteins c-akt (metabolism)</term>
<term>Ras Homolog Enriched in Brain Protein (genetics)</term>
<term>Ras Homolog Enriched in Brain Protein (metabolism)</term>
<term>Repressor Proteins (genetics)</term>
<term>Repressor Proteins (metabolism)</term>
<term>Signal Transduction (MeSH)</term>
<term>T-Lymphocytes (metabolism)</term>
<term>T-Lymphocytes (virology)</term>
<term>Tuberous Sclerosis Complex 1 Protein (MeSH)</term>
<term>Tumor Suppressor Proteins (genetics)</term>
<term>Tumor Suppressor Proteins (metabolism)</term>
<term>Virus Activation (MeSH)</term>
<term>Virus Latency (MeSH)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr">
<term>Activation virale (MeSH)</term>
<term>Complexe-1 cible mécanistique de la rapamycine (génétique)</term>
<term>Complexe-1 cible mécanistique de la rapamycine (métabolisme)</term>
<term>Humains (MeSH)</term>
<term>Infections à VIH (enzymologie)</term>
<term>Infections à VIH (génétique)</term>
<term>Infections à VIH (métabolisme)</term>
<term>Infections à VIH (virologie)</term>
<term>Interactions hôte-pathogène (MeSH)</term>
<term>Latence virale (MeSH)</term>
<term>Lignée cellulaire (MeSH)</term>
<term>Lymphocytes T (métabolisme)</term>
<term>Lymphocytes T (virologie)</term>
<term>Protéine homologue de Ras enrichie dans le cerveau (génétique)</term>
<term>Protéine homologue de Ras enrichie dans le cerveau (métabolisme)</term>
<term>Protéine-1 du complexe de la sclérose tubéreuse (MeSH)</term>
<term>Protéines G monomériques (génétique)</term>
<term>Protéines G monomériques (métabolisme)</term>
<term>Protéines de répression (génétique)</term>
<term>Protéines de répression (métabolisme)</term>
<term>Protéines proto-oncogènes c-akt (génétique)</term>
<term>Protéines proto-oncogènes c-akt (métabolisme)</term>
<term>Protéines suppresseurs de tumeurs (génétique)</term>
<term>Protéines suppresseurs de tumeurs (métabolisme)</term>
<term>Transduction du signal (MeSH)</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (génétique)</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (physiologie)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en">
<term>Mechanistic Target of Rapamycin Complex 1</term>
<term>Monomeric GTP-Binding Proteins</term>
<term>Proto-Oncogene Proteins c-akt</term>
<term>Ras Homolog Enriched in Brain Protein</term>
<term>Repressor Proteins</term>
<term>Tumor Suppressor Proteins</term>
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<keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr">
<term>Infections à VIH</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en">
<term>HIV Infections</term>
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<keywords scheme="MESH" qualifier="genetics" xml:lang="en">
<term>HIV Infections</term>
<term>HIV-1</term>
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<keywords scheme="MESH" qualifier="génétique" xml:lang="fr">
<term>Complexe-1 cible mécanistique de la rapamycine</term>
<term>Infections à VIH</term>
<term>Protéine homologue de Ras enrichie dans le cerveau</term>
<term>Protéines G monomériques</term>
<term>Protéines de répression</term>
<term>Protéines proto-oncogènes c-akt</term>
<term>Protéines suppresseurs de tumeurs</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en">
<term>HIV Infections</term>
<term>Mechanistic Target of Rapamycin Complex 1</term>
<term>Monomeric GTP-Binding Proteins</term>
<term>Proto-Oncogene Proteins c-akt</term>
<term>Ras Homolog Enriched in Brain Protein</term>
<term>Repressor Proteins</term>
<term>T-Lymphocytes</term>
<term>Tumor Suppressor Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>Complexe-1 cible mécanistique de la rapamycine</term>
<term>Infections à VIH</term>
<term>Lymphocytes T</term>
<term>Protéine homologue de Ras enrichie dans le cerveau</term>
<term>Protéines G monomériques</term>
<term>Protéines de répression</term>
<term>Protéines proto-oncogènes c-akt</term>
<term>Protéines suppresseurs de tumeurs</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr">
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
</keywords>
<keywords scheme="MESH" qualifier="physiology" xml:lang="en">
<term>HIV-1</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr">
<term>Infections à VIH</term>
<term>Lymphocytes T</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en">
<term>HIV Infections</term>
<term>T-Lymphocytes</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Cell Line</term>
<term>Host-Pathogen Interactions</term>
<term>Humans</term>
<term>Signal Transduction</term>
<term>Tuberous Sclerosis Complex 1 Protein</term>
<term>Virus Activation</term>
<term>Virus Latency</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr">
<term>Activation virale</term>
<term>Humains</term>
<term>Interactions hôte-pathogène</term>
<term>Latence virale</term>
<term>Lignée cellulaire</term>
<term>Protéine-1 du complexe de la sclérose tubéreuse</term>
<term>Transduction du signal</term>
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<div type="abstract" xml:lang="en">The latent reservoir of HIV-1 presents a major barrier to viral eradication. The mechanism of the establishment and maintenance of the latent viral reservoir is not yet fully understood, which hinders the development of effective curative strategies. In this study, we identified two inhibitory genes, TSC1 and DEPDC5, that maintained HIV-1 latency by suppressing the mTORC1 pathway. We first adapted a genome-wide CRISPR screening approach to identify host factors required for HIV latency in a T-cell-based latency model and discovered two inhibitory genes, TSC1 and DEPDC5, which are potentially involved in HIV-1 latency. Knockout of either TSC1 or DEPDC5 led to enhanced HIV-1 reactivation in both a T-cell line (C11) and a monocyte cell line (U1), and this enhancement could be antagonized by the mTORC1 inhibitor rapamycin. Further evaluation of the mechanism revealed that TSC1 suppresses AKT-mTORC1-S6 via downregulation of Rheb, whereas DEPDC5 inhibits AKT-mTORC1-S6 through RagA. Overall, both TSC1 and DEPDC5 negatively regulate the AKT-mTORC1 pathway, and thus their agonists could be used in the development of new therapeutic approaches for activating HIV-1 latency.</div>
</front>
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<Year>2018</Year>
<Month>11</Month>
<Day>02</Day>
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<Year>2018</Year>
<Month>12</Month>
<Day>02</Day>
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<Month>Aug</Month>
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<Title>Emerging microbes & infections</Title>
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<Abstract>
<AbstractText>The latent reservoir of HIV-1 presents a major barrier to viral eradication. The mechanism of the establishment and maintenance of the latent viral reservoir is not yet fully understood, which hinders the development of effective curative strategies. In this study, we identified two inhibitory genes, TSC1 and DEPDC5, that maintained HIV-1 latency by suppressing the mTORC1 pathway. We first adapted a genome-wide CRISPR screening approach to identify host factors required for HIV latency in a T-cell-based latency model and discovered two inhibitory genes, TSC1 and DEPDC5, which are potentially involved in HIV-1 latency. Knockout of either TSC1 or DEPDC5 led to enhanced HIV-1 reactivation in both a T-cell line (C11) and a monocyte cell line (U1), and this enhancement could be antagonized by the mTORC1 inhibitor rapamycin. Further evaluation of the mechanism revealed that TSC1 suppresses AKT-mTORC1-S6 via downregulation of Rheb, whereas DEPDC5 inhibits AKT-mTORC1-S6 through RagA. Overall, both TSC1 and DEPDC5 negatively regulate the AKT-mTORC1 pathway, and thus their agonists could be used in the development of new therapeutic approaches for activating HIV-1 latency.</AbstractText>
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<name sortKey="He, Qian" sort="He, Qian" uniqKey="He Q" first="Qian" last="He">Qian He</name>
<name sortKey="Liao, Qibin" sort="Liao, Qibin" uniqKey="Liao Q" first="Qibin" last="Liao">Qibin Liao</name>
<name sortKey="Xu, Jianqing" sort="Xu, Jianqing" uniqKey="Xu J" first="Jianqing" last="Xu">Jianqing Xu</name>
<name sortKey="Xu, Jianqing" sort="Xu, Jianqing" uniqKey="Xu J" first="Jianqing" last="Xu">Jianqing Xu</name>
<name sortKey="Zhang, Linxia" sort="Zhang, Linxia" uniqKey="Zhang L" first="Linxia" last="Zhang">Linxia Zhang</name>
<name sortKey="Zhang, Xiaoyan" sort="Zhang, Xiaoyan" uniqKey="Zhang X" first="Xiaoyan" last="Zhang">Xiaoyan Zhang</name>
<name sortKey="Zhu, Huanzhang" sort="Zhu, Huanzhang" uniqKey="Zhu H" first="Huanzhang" last="Zhu">Huanzhang Zhu</name>
</country>
</tree>
</affiliations>
</record>

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