Lysine acetylation of DosR regulates the hypoxia response of <i>Mycobacterium tuberculosis</i>

Tuberculosis caused by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) infection remains a large global public health problem. One striking characteristic of <i>Mtb</i> is its ability to adapt to hypoxia and trigger the ensuing transition to a dormant state for persistent infection, but how the hypoxia response of <i>Mtb</i> is regulated remains largely unknown. Here we performed a quantitative acetylome analysis to compare the acetylation profile of <i>Mtb</i> under aeration and hypoxia, and showed that 377 acetylation sites in 269 <i>Mtb</i> proteins were significantly changed under hypoxia. In particular, deacetylation of dormancy survival regulator (DosR) at K182 promoted the hypoxia response in <i>Mtb</i> and enhanced the transcription of DosR-targeted genes. Mechanistically, recombinant DosR^K182R protein demonstrated enhanced DNA-binding activity in comparison with DosR^K182Q protein. Moreover, Rv0998 was identified as an acetyltransferase that mediates the acetylation of DosR at K182. Deletion of Rv0998 also promoted the adaptation of <i>Mtb</i> to hypoxia and the transcription of DosR-targeted genes. Mice infected with an <i>Mtb</i> strain containing acetylation-defective DosR^K182R had much lower bacterial counts and less severe histopathological impairments compared with those infected with the wild-type strain. Our findings suggest that hypoxia induces the deacetylation of DosR, which in turn increases its DNA-binding ability to promote the transcription of target genes, allowing <i>Mtb</i> to shift to dormancy under hypoxia.