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MiR-25 blunts autophagy and promotes the survival of Mycobacterium tuberculosis by regulating NPC1.

ABSTRACT: Mycobacterium tuberculosis (Mtb) evades host clearance by inhibiting autophagy. MicroRNA-25 (miR-25) expression was significantly up-regulated in the lung tissues of mice infected with Bacillus Calmette-Guerin (BCG) and macrophages infected with Mtb or BCG, especially in the early stages of infection. MiR-25 can significantly increase the survival of Mtb and BCG in macrophages. We validated that miR-25 targets the NPC1 protein located on the lysosomal membrane, resulting in damage to lysosomal function, thereby inhibiting autophagolysosome formation and promoting the survival of Mtb and BCG. Consistently, mice lacking miR-25 exhibited more resistant to BCG infection. In addition, we found that Rv1759c induces the expression of miR-25 through NFKB inhibitor zeta (NFKBIZ). This study demonstrates that the role of miR-25 during Mtb infection contributes to a better understanding of the pathogenesis of tuberculosis (TB).

SUBMITTER: Dong W

PROVIDER: S-EPMC9108763 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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MiR-25 blunts autophagy and promotes the survival of <i>Mycobacterium tuberculosis</i> by regulating NPC1.

Dong Wenqi W Wang Gaoyan G Feng Jiajia J Li Pei P Wang Rui R Lu Hao H Lu Wenjia W Wang Chenchen C Wang Xiangru X Chen Huanchun H Xiang Yaozu Y Tan Chen C

iScience 20220422 5

<i>Mycobacterium tuberculosis</i> (Mtb) evades host clearance by inhibiting autophagy. MicroRNA-25 (miR-25) expression was significantly up-regulated in the lung tissues of mice infected with Bacillus Calmette-Guerin (BCG) and macrophages infected with Mtb or BCG, especially in the early stages of infection. MiR-25 can significantly increase the survival of Mtb and BCG in macrophages. We validated that miR-25 targets the NPC1 protein located on the lysosomal membrane, resulting in damage to lyso ...[more]

PMID: 35586071

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Project description:Autophagy is a primordial eukaryotic pathway, which provides the immune system with multiple mechanisms for the elimination of invading pathogens including Mycobacterium tuberculosis (Mtb). As a consequence, Mtb has evolved different strategies to hijack the autophagy process. Given the crucial role of human primary dendritic cells (DC) in host immunity control, we characterized Mtb-DC interplay by studying the contribution of cellular microRNAs (miRNAs) in the post-transcriptional regulation of autophagy related genes. From the expression profile of de-regulated miRNAs obtained in Mtb-infected human DC, we identified 7 miRNAs whose expression was previously found to be altered in specimens of TB patients. Among them, gene ontology analysis showed that miR-155, miR-155* and miR-146a target mRNAs with a significant enrichment in biological processes linked to autophagy. Interestingly, miR-155 was significantly stimulated by live and virulent Mtb and enriched in polysome-associated RNA fraction, where actively translated mRNAs reside. The putative pair interaction among the E2 conjugating enzyme involved in LC3-lipidation and autophagosome formation-ATG3-and miR-155 arose by target prediction analysis, was confirmed by both luciferase reporter assay and Atg3 immunoblotting analysis of miR-155-transfected DC, which showed also a consistent Atg3 protein and LC3 lipidated form reduction. Late in infection, when miR-155 expression peaked, both the level of Atg3 and the number of LC3 puncta per cell (autophagosomes) decreased dramatically. In accordance, miR-155 silencing rescued autophagosome number in Mtb infected DC and enhanced autolysosome fusion, thereby supporting a previously unidentified role of the miR-155 as inhibitor of ATG3 expression. Taken together, our findings suggest how Mtb can manipulate cellular miRNA expression to regulate Atg3 for its own survival, and highlight the importance to develop novel therapeutic strategies against tuberculosis that would boost autophagy.

Dataset Information

MiR-25 blunts autophagy and promotes the survival of Mycobacterium tuberculosis by regulating NPC1.

Publications

MiR-25 blunts autophagy and promotes the survival of <i>Mycobacterium tuberculosis</i> by regulating NPC1.

Similar Datasets

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