Unraveling novel roles of the Mycobacterium tuberculosis transcription factor Rv0081 in regulation of the nucleoid-associated proteins Lsr2 and EspR, cholesterol utilization, and subversion of lysosomal trafficking in macrophages,Molecular Microbiology

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Unraveling novel roles of the Mycobacterium tuberculosis transcription factor Rv0081 in regulation of the nucleoid-associated proteins Lsr2 and EspR, cholesterol utilization, and subversion of lysosomal trafficking in macrophages
Molecular Microbiology ( IF 2.6 ) Pub Date : 2022-03-19 , DOI: 10.1111/mmi.14895
Suruchi Lata ₁ , Amar Chandra Mahatha ₁ , Soumya Mal ₁ , Umesh D Gupta ₂ , Manikuntala Kundu ₁ , Joyoti Basu ₁

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The transcriptional network of Mycobacterium tuberculosis is designed to enable the organism to withstand host-associated stresses and to exploit the host milieu for its own survival and multiplication. Rv0081 (MT0088) is a transcriptional regulator whose interplay with other gene regulatory proteins and role in enabling M. tuberculosis to thrive within its host is incompletely understood. M. tuberculosis utilizes cholesterol within the granuloma. We show that deletion of Rv0081 compromises the ability of M. tuberculosis to utilize cholesterol as the sole carbon source, to subvert lysosomal trafficking, and to form granulomas in vitro. Rv0081 downregulates expression of the nucleoid-associated repressor Lsr2, leading to increased expression of the cholesterol catabolism-linked gene kshA and genes of the cholesterol importing operon, accounting for the requirement of Rv0081 in cholesterol utilization. Furthermore, Rv0081 activates EspR which is required for secretion of ESX-1 substrates, which in turn are involved in subversion of lysosomal trafficking of M. tuberculosis and granuloma expansion. These results provide new insight into the role of Rv0081 under conditions which resemble the environment encountered by M. tuberculosis within its host. Rv0081 emerges as a central regulator of genes linked to various pathways which are crucial for the survival of the bacterium in vivo.

中文翻译：

揭示结核分枝杆菌转录因子 Rv0081 在调节类核相关蛋白 Lsr2 和 EspR、胆固醇利用和破坏巨噬细胞溶酶体运输中的新作用

结核分枝杆菌的转录网络旨在使生物体能够承受与宿主相关的压力，并利用宿主环境来实现自身的生存和繁殖。Rv0081 (MT0088) 是一种转录调节因子，它与其他基因调节蛋白的相互作用以及在使结核分枝杆菌在其宿主内茁壮成长方面的作用尚不完全清楚。结核分枝杆菌利用肉芽肿内的胆固醇。我们表明Rv0081的缺失会损害M. tuberculosis的能力利用胆固醇作为唯一碳源，破坏溶酶体运输，并在体外形成肉芽肿。Rv0081 下调类核相关阻遏物 Lsr2 的表达，导致胆固醇分解代谢相关基因kshA和胆固醇输入操纵子基因的表达增加，这说明了 Rv0081 在胆固醇利用中的需要。此外，Rv0081 激活了 ESX-1 底物分泌所需的 EspR，而 ESX-1 底物反过来又参与破坏结核分枝杆菌的溶酶体运输和肉芽肿扩张。这些结果为 Rv0081 在类似于结核分枝杆菌遇到的环境的条件下的作用提供了新的见解在其宿主内。Rv0081 成为与各种途径相关的基因的中心调节因子，这些途径对细菌在体内的存活至关重要。

更新日期：2022-03-19

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