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
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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.

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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。
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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
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