Junfeng Zhen
Yuzhu Li
Yu Huang
Xuefeng Ai
Yue Li
Andrea Stojkoska
Xue Huang
Cao Ruan
Jiang Li
Lin Fan
Jianping Xie
a Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Ministry of Education Eco-Environment of the Three Gorges Reservoir Region, School of Life Sciences, Southwest University, Chongqing 400715, China;
b Shanghai Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai Key Laboratory of Tuberculosis, Shanghai 200433, China
Funds: We thank Quanxin Long for providing some instrument support, LongXiang Xie, Xiangke Duan, and Qiming Li for academic advice, and anonymous reviewers for professional advice and recognition of this work. This work was supported by the National Natural Science Foundation of China (82072246, 81871182), National key R&D plan (2016YFC0502304).
Received Date: 2020-10-19
Accepted Date:2021-06-22
Rev Recd Date:2021-06-20
Publish Date:2021-11-20
Abstract
Abstract
L-Arginine is the precursor of nitric oxide (NO), a host immune effector against intracellular pathogens including Mycobacterium tuberculosis (M. tb). Pathogens including M. tb have evolved various strategies targeting arginine to block the production of NO for better survival and proliferation. However, L-arginine metabolism and regulation in Mycobacterium are poorly understood. Here, we report the identification of M. smegmatis MSMEG_1415 (homolog of M. tb Rv2324) as an arginine-responsive transcriptional factor regulating the arginase pathway. In the absence of L-arginine, MSMEG_1415 acts as a repressor to inhibit the transcription of the roc (for arginine, ornithine catabolism) gene cluster, thereby switching off the arginase pathway. Treatment with L-arginine relieves the transcriptional inhibition of MSMEG_1415 on the roc gene cluster to activate the arginase pathway. Moreover, the L-arginine-MSMEG_1415 complex activates the transcription of the roc gene cluster by recognizing and binding a 15-bp palindrome motif, thereby preventing the excess accumulation of L-arginine in M. smegmatis. Physiologically, MSMEG_1415 confers mycobacteria resistance to starvation and fluoroquinolones exposure, suggestive of its important role in M. smegmatis persistence. The results uncover a unique regulatory mechanism of arginine metabolism in mycobacteria and identify M. tb Rv2324 as an attractive candidate target for the design of drugs against tuberculosis.Keywords: Mycobacterium tuberculosis,
Lrp/AsnC family transcriptional regulator,
Repressor,
Arginine,
Arginase pathway,
Persistence
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