Membrane Biology
MtrP, a putative methyltransferase in Corynebacteria, is required for optimal membrane transport of trehalose mycolates

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Pathogenic bacteria of the genera Mycobacterium and Corynebacterium cause severe human diseases such as tuberculosis (Mycobacterium tuberculosis) and diphtheria (Corynebacterium diphtheriae). The cells of these species are surrounded by protective cell walls rich in long-chain mycolic acids. These fatty acids are conjugated to the disaccharide trehalose on the cytoplasmic side of the bacterial cell membrane. They are then transported across the membrane to the periplasm where they act as donors for other reactions. We have previously shown that transient acetylation of the glycolipid trehalose monohydroxycorynomycolate (hTMCM) enables its efficient transport to the periplasm in Corynebacterium glutamicum and that acetylation is mediated by the membrane protein TmaT. Here, we show that a putative methyltransferase, encoded at the same genetic locus as TmaT, is also required for optimal hTMCM transport. Deletion of the C. glutamicum gene NCgl2764 (Rv0224c in M. tuberculosis) abolished acetyltrehalose monocorynomycolate (AcTMCM) synthesis, leading to accumulation of hTMCM in the inner membrane and delaying its conversion to trehalose dihydroxycorynomycolate (h2TDCM). Complementation with NCgl2764 normalized turnover of hTMCM to h2TDCM. In contrast, complementation with NCgl2764 derivatives mutated at residues essential for methyltransferase activity failed to rectify the defect, suggesting that NCgl2764/Rv0224c encodes a methyltransferase, designated here as MtrP. Comprehensive analyses of the individual mtrP and tmaT mutants and of a double mutant revealed strikingly similar changes across several lipid classes compared with WT bacteria. These findings indicate that both MtrP and TmaT have nonredundant roles in regulating AcTMCM synthesis, revealing additional complexity in the regulation of trehalose mycolate transport in the Corynebacterineae.

Mycobacterium tuberculosis
cell wall
lipid bilayer
fatty acid
microbiology
Corynebacterium
glutamicum

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This work was supported by National Health and Medical Research Council of Australia Project Grant 1064466 (to P. K. C., R. L. C., and M. J. M.), Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics Grant COE562063 (to R. L. C.), and Australian Research Council Discovery Grant 180102463 (to R. L. C. and M. J. M.). The authors declare that they have no conflicts of interest with the contents of this article.

This article contains Figs. S1–S6.

1

Both authors contributed equally as first authors.

2

Present address: The Florey Institute of Neuroscience and Mental Health, Melbourne Dementia Research Centre, University of Melbourne, 30 Royal Parade, Parkville, Victoria 3052, Australia.

3

Present address: ApicoLipid Team, Institute for Advanced Biosciences, Université Grenoble Alpes, CNRS UMR5309, INSERM U1209, Grenoble, France.

4

These authors contributed equally as senior authors.