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. 2023 Mar;290(6):1583-1595.
doi: 10.1111/febs.16647. Epub 2022 Oct 17.

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

Akhil Raj Pushparajan  1   2 , Lekshmi K Edison  1 , Ramakrishnan Ajay Kumar  1
Affiliations
Free article

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

Akhil Raj Pushparajan et al. FEBS J. 2023 Mar.
Free article

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 immunocompromised conditions. Transcriptional regulation in intracellular pathogens plays an important role in their 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) which encode DNA repair proteins and negatively regulates the expression of these genes. In the present study, we show that Rv1019 regulates the expression of the genes Rv3230c and Rv3229c (desA3) also which form a two-gene operon in M. tuberculosis. Overexpression of Rv1019 in M. tuberculosis significantly downregulated the expression of these genes. Employing Wayne's hypoxia-induced dormancy model of M. tuberculosis, we show that Rv1019 is upregulated three-fold under hypoxia. Finally, by reporter assay, using Mycobacterium 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.

Keywords: Mycobacterium tuberculosis; dormancy; hypoxia; operon; transcriptional regulator.

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