Single START-domain protein Mtsp17 is involved in transcriptional regulation in Mycobacterium smegmatis

Abstract

Tuberculosis caused by the pathogen Mycobacterium tuberculosis (MTB), remains a significant threat to global health. Elucidating the mechanisms of essential MTB genes provides an important theoretical basis for drug exploitation. Gene mtsp17 is essential and is conserved in the Mycobacterium genus. Although Mtsp17 has a structure closely resembling typical steroidogenic acute regulatory protein-related lipid transfer (START) family proteins, its biological function is different. This study characterizes the transcriptomes of Mycobacterium smegmatis to explore the consequences of mtsp17 downregulation on gene expression. Suppression of the mtsp17 gene resulted in significant down-regulation of 3% and upregulation of 1% of all protein-coding genes. Expression of desA1, an essential gene involved in mycolic acid synthesis, and the anti-SigF antagonist MSMEG_0586 were down-regulated in the conditional Mtsp17 knockout mutant and up-regulated in the Mtsp17 over-expression strain. Trends in the changes of 70 of the 79 differentially expressed genes (Log2 fold change > 1.5) in the conditional Mtsp17 knockout strain were the same as in the SigF knockout strain. Our data suggest that Mtsp17 is likely an activator of desA1 and Mtsp17 regulates the SigF regulon by SigF regulatory pathways through the anti-SigF antagonist MSMEG_0586. Our findings indicate the role of Mtsp17 may be in transcriptional regulation, provide new insights into the molecular mechanisms of START family proteins, and uncover a new node in the regulatory network of mycobacteria.

Modulating mycobacterial envelope integrity for antibiotic synergy with benzothiazoles

“…The biological function of Rv0164 is unknown to date. However, several studies have investigated its homolog in M. smegmatis, MSMEG_0129 (Zheng et al, 2017(Zheng et al, , 2018Zhou et al, 2020Zhou et al, , 2021, which shares 59% identity with Rv0164. These proteins are classified as polyketide aromatase/cyclase family members of the steroidogenic acute regulatory protein-related lipid transfer (START) domain superfamily based on sequence alignment (Zheng et al, 2018).…”

“…For instance, nutrient deficiency led to the down-regulation of MSMEG_0129 and Clp2 and the up-regulation of CarD. A recent study mapped the transcriptional profile of strains with the decreased expression of msmeg_0129 and found numerous genes involved in cell wall biosynthesis and metabolism to be differentially expressed, leading the authors to propose that MSMEG_0129 might coordinate signal transfer during stress responses ( Zhou et al, 2021 ). It remains to be confirmed whether the same is true for Rv0164.…”

Domain swapping of the C‐terminal helix promotes the dimerization of a novel ribonuclease protein from Mycobacterium tuberculosis

“…This function is predicted to be active in the Rv1546 dimer. Although the functions of START domain proteins in M. tuberculosis remain undetermined, some research papers showed that the proteins are essential for bacterial growth and survival (Zhou et al, 2020(Zhou et al, , 2021. Therefore, in consideration of structural features and homologs of Rv1546, Rv1546 has a potential to be a novel drug target against TB.…”

“…In prokaryotes, the START domain is found in polyketide ARO/CYC proteins. Although plant and mammalian proteins containing the START domain have been shown to function in lipid binding or the modulation transcription factor activity (Schrick et al, 2014), these functions were not well known in prokaryotes until recent studies elucidated their transcriptional regulatory function in M. tuberculosis (Zheng et al, 2018;Zhou et al, 2021). In addition to this native property, the domain-swapped dimer structure might confer a new function, such as ribonuclease activity, on Rv1546.…”