ABSTRACT Zinc is a microelement essential for the growth of almost all organisms, but it is toxic at high concentrations and represents an antimicrobial strategy for macrophages. Mycobacterium tuberculosis and Mycobacterium bovis are two well-known intracellular pathogens with strong environmental adaptability, including zinc toxicity. However, the signaling pathway and molecular mechanisms on sensing and resistance to zinc toxicity remains unclear in mycobacteria. Here, we first report that P1B-type ATPase CtpG acts as a zinc efflux transporter and characterize a novel CmtR-CtpG-Zn2+ regulatory pathway that enhances mycobacterial resistance to zinc toxicity. We found that zinc upregulates ctpG expression via transcription factor CmtR and stimulates the ATPase activity of CtpG. The APC residues in TM6 is essential for CtpG to export zinc and enhance M. bovis BCG resistance to zinc toxicity. During infection, CtpG inhibits zinc accumulation in the mycobacteria, and aids bacterial survival in THP-1 macrophage and mice with elevated inflammatory responses. Our findings revealed the existence of a novel regulatory pathway on mycobacteria responding to and adapting to host-mediated zinc toxicity. IMPORTANCE Tuberculosis is caused by the bacillus Mycobacterium tuberculosis and is one of the major sources of mortality. M. tuberculosis has developed unique mechanisms to adapt to host environments, including zinc deficiency and toxicity, during infection. However, the molecular mechanism by which mycobacteria promote detoxification of zinc, and the associated signaling pathways remains largely unclear. In this study, we first report that P1B-type ATPase CtpG acts as a zinc efflux transporter and characterize a novel CmtR-CtpG-Zn2+ regulatory pathway that enhances mycobacterial resistance to zinc toxicity in M. bovis. Our findings reveal the existence of a novel excess zinc-triggered signaling circuit, provide new insights into mycobacterial adaptation to the host environment during infection, and might be useful targets for the treatment of tuberculosis.
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