NCoR1 controls Mycobacterium tuberculosis growth in myeloid cells by regulating the AMPK-mTOR-TFEB axis.

IF 7.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY PLoS Biology Pub Date : 2023-08-17 eCollection Date: 2023-08-01 DOI:10.1371/journal.pbio.3002231
Viplov Kumar Biswas, Kaushik Sen, Abdul Ahad, Arup Ghosh, Surbhi Verma, Rashmirekha Pati, Subhasish Prusty, Sourya Prakash Nayak, Sreeparna Podder, Dhiraj Kumar, Bhawna Gupta, Sunil Kumar Raghav
{"title":"NCoR1 controls Mycobacterium tuberculosis growth in myeloid cells by regulating the AMPK-mTOR-TFEB axis.","authors":"Viplov Kumar Biswas,&nbsp;Kaushik Sen,&nbsp;Abdul Ahad,&nbsp;Arup Ghosh,&nbsp;Surbhi Verma,&nbsp;Rashmirekha Pati,&nbsp;Subhasish Prusty,&nbsp;Sourya Prakash Nayak,&nbsp;Sreeparna Podder,&nbsp;Dhiraj Kumar,&nbsp;Bhawna Gupta,&nbsp;Sunil Kumar Raghav","doi":"10.1371/journal.pbio.3002231","DOIUrl":null,"url":null,"abstract":"<p><p>Mycobacterium tuberculosis (Mtb) defends host-mediated killing by repressing the autophagolysosome machinery. For the first time, we report NCoR1 co-repressor as a crucial host factor, controlling Mtb growth in myeloid cells by regulating both autophagosome maturation and lysosome biogenesis. We found that the dynamic expression of NCoR1 is compromised in human peripheral blood mononuclear cells (PBMCs) during active Mtb infection, which is rescued upon prolonged anti-mycobacterial therapy. In addition, a loss of function in myeloid-specific NCoR1 considerably exacerbates the growth of M. tuberculosis in vitro in THP1 differentiated macrophages, ex vivo in bone marrow-derived macrophages (BMDMs), and in vivo in NCoR1MyeKO mice. We showed that NCoR1 depletion controls the AMPK-mTOR-TFEB signalling axis by fine-tuning cellular adenosine triphosphate (ATP) homeostasis, which in turn changes the expression of proteins involved in autophagy and lysosomal biogenesis. Moreover, we also showed that the treatment of NCoR1 depleted cells by Rapamycin, Antimycin-A, or Metformin rescued the TFEB activity and LC3 levels, resulting in enhanced Mtb clearance. Similarly, expressing NCoR1 exogenously rescued the AMPK-mTOR-TFEB signalling axis and Mtb killing. Overall, our data revealed a central role of NCoR1 in Mtb pathogenesis in myeloid cells.</p>","PeriodicalId":20240,"journal":{"name":"PLoS Biology","volume":"21 8","pages":"e3002231"},"PeriodicalIF":7.8000,"publicationDate":"2023-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10465006/pdf/","citationCount":"2","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"PLoS Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1371/journal.pbio.3002231","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/8/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 2

Abstract

Mycobacterium tuberculosis (Mtb) defends host-mediated killing by repressing the autophagolysosome machinery. For the first time, we report NCoR1 co-repressor as a crucial host factor, controlling Mtb growth in myeloid cells by regulating both autophagosome maturation and lysosome biogenesis. We found that the dynamic expression of NCoR1 is compromised in human peripheral blood mononuclear cells (PBMCs) during active Mtb infection, which is rescued upon prolonged anti-mycobacterial therapy. In addition, a loss of function in myeloid-specific NCoR1 considerably exacerbates the growth of M. tuberculosis in vitro in THP1 differentiated macrophages, ex vivo in bone marrow-derived macrophages (BMDMs), and in vivo in NCoR1MyeKO mice. We showed that NCoR1 depletion controls the AMPK-mTOR-TFEB signalling axis by fine-tuning cellular adenosine triphosphate (ATP) homeostasis, which in turn changes the expression of proteins involved in autophagy and lysosomal biogenesis. Moreover, we also showed that the treatment of NCoR1 depleted cells by Rapamycin, Antimycin-A, or Metformin rescued the TFEB activity and LC3 levels, resulting in enhanced Mtb clearance. Similarly, expressing NCoR1 exogenously rescued the AMPK-mTOR-TFEB signalling axis and Mtb killing. Overall, our data revealed a central role of NCoR1 in Mtb pathogenesis in myeloid cells.

Abstract Image

Abstract Image

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
NCoR1通过调节AMPK-mTOR TFEB轴来控制结核分枝杆菌在骨髓细胞中的生长。
结核分枝杆菌(Mtb)通过抑制自噬溶酶体机制来防御宿主介导的杀伤。我们首次报道了NCoR1共阻遏物作为一种关键的宿主因子,通过调节自噬体成熟和溶酶体生物发生来控制骨髓细胞中Mtb的生长。我们发现,在活动性结核分枝杆菌感染期间,人类外周血单核细胞(PBMC)中NCoR1的动态表达受到损害,经过长期的抗分枝杆菌治疗后,这种情况得以挽救。此外,髓系特异性NCoR1的功能丧失显著加剧了结核分枝杆菌在体外THP1分化巨噬细胞、离体骨髓衍生巨噬细胞(BMDM)和体内NCoR1MyeKO小鼠中的生长。我们发现,NCoR1缺失通过微调细胞三磷酸腺苷(ATP)稳态来控制AMPK-mTOR TFEB信号轴,从而改变参与自噬和溶酶体生物发生的蛋白质的表达。此外,我们还表明,用雷帕霉素、抗霉素-A或二甲双胍处理NCoR1缺失的细胞可以挽救TFEB活性和LC3水平,从而提高Mtb清除率。类似地,外源性表达NCoR1挽救了AMPK-mTOR TFEB信号轴和Mtb杀伤。总体而言,我们的数据揭示了NCoR1在骨髓细胞Mtb发病机制中的核心作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
PLoS Biology
PLoS Biology 生物-生化与分子生物学
CiteScore
14.40
自引率
2.00%
发文量
359
审稿时长
3 months
期刊介绍: PLOS Biology is an open-access, peer-reviewed general biology journal published by PLOS, a nonprofit organization of scientists and physicians dedicated to making the world's scientific and medical literature freely accessible. The journal publishes new articles online weekly, with issues compiled and published monthly. ISSN Numbers: eISSN: 1545-7885 ISSN: 1544-9173
期刊最新文献
Functional network modules overlap and are linked to interindividual connectome differences during human brain development Plasmodium RON11 triggers biogenesis of the merozoite rhoptry pair and is essential for erythrocyte invasion Organelle landscape analysis using a multiparametric particle-based method Integration of estimated regional gene expression with neuroimaging and clinical phenotypes at biobank scale Alveolin proteins in the Toxoplasma inner membrane complex form a highly interconnected structure that maintains parasite shape and replication
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1