Mycobacterium Lrp/AsnC family transcriptional factor modulates the arginase pathway as both a sensor and a transcriptional repressor  

作　　者：Shuangquan Yan Junfeng Zhen Yuzhu Li Yu Huang Xuefeng Ai Yue Li Andrea Stojkoska Xue Huang Cao Ruan Jiang Li Lin Fan Jianping Xie 

机构地区：[1]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 [2]Shanghai Clinic and Research Center of Tuberculosis,Shanghai Pulmonary Hospital,Tongji University School of Medicine,Shanghai Key Laboratory of Tuberculosis,Shanghai 200433,China

出　　处：《Journal of Genetics and Genomics》2021年第11期1020-1031,共12页遗传学报（英文版）

基　　金：the National Natural Science Foundation of China(82072246,81871182);National key R&D plan(2016YFC0502304).

摘　　要：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.

关 键 词：Mycobacterium tuberculosis Lrp/AsnC family transcriptional regulator REPRESSOR Arginine Arginase pathway Persistence 

分 类 号：R378.91[医药卫生—病原生物学]