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

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.