Mycobacterium tuberculosis transcriptional regulator Rv1019 is upregulated in hypoxia and negatively regulates Rv3230c-Rv3229c operon encoding enzymes in the oleic acid biosynthetic pathway

Abstract

The main obstacle in eradicating tuberculosis is the ability of Mycobacterium tuberculosis to remain dormant in the host, and then to get reactivated even years later under immuno-compromised conditions. Transcriptional regulation in intracellular pathogens plays an important role in adapting to the challenging environment inside the host cells. Previously, we demonstrated that Rv1019, a putative transcriptional regulator of M. tuberculosis H37Rv, is an autorepressor. We showed that, Rv1019 is cotranscribed with Rv1020 (mfd) and Rv1021 (mazG) encoding DNA repair proteins and negatively regulates the expression of these genes. In the present study, we show that Rv1019 also regulates the expression of the genes Rv3230c and Rv3229c (desA3) which form a two-gene operon in M. tuberculosis. Constitutive expression of Rv1019 in M. tuberculosis significantly downregulated the expression of these genes. Employing Waynes hypoxia-induced dormancy model of M. tuberculosis, we show that Rv1019 is upregulated (3-fold) under hypoxia. Finally, by reporter assay, using M. smegmatis as a model, we validate that Rv1019 is recruited to the promoter of Rv3230c-Rv3229c during hypoxia and negatively regulates this operon which is involved in the biosynthesis of oleic acid.