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MBio. 2019 Jun 25;10(3). pii: e00850-19. doi: 10.1128/mBio.00850-19.

Two Accessory Proteins Govern MmpL3 Mycolic Acid Transport in Mycobacteria.

Author information

1
Immunology Program, Sloan Kettering Institute, New York, New York, USA.
2
Program for Microbial Pathogenesis, University of California, San Francisco, San Francisco, California, USA.
3
Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
4
Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, New York, USA.
5
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA.
6
Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, California, USA.
7
The J. David Gladstone Institutes, San Francisco, California, USA.
8
Chan-Zuckerberg Biohub, San Francisco, California, USA.
9
Immunology Program, Sloan Kettering Institute, New York, New York, USA glickmam@mskcc.org.
10
Division of Infectious Diseases, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
11
Immunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, New York, USA.

Abstract

Mycolic acids are the signature lipid of mycobacteria and constitute an important physical component of the cell wall, a target of mycobacterium-specific antibiotics and a mediator of Mycobacterium tuberculosis pathogenesis. Mycolic acids are synthesized in the cytoplasm and are thought to be transported to the cell wall as a trehalose ester by the MmpL3 transporter, an antibiotic target for M. tuberculosis However, the mechanism by which mycolate synthesis is coupled to transport, and the full MmpL3 transport machinery, is unknown. Here, we identify two new components of the MmpL3 transport machinery in mycobacteria. The protein encoded by MSMEG_0736/Rv0383c is essential for growth of Mycobacterium smegmatis and M. tuberculosis and is anchored to the cytoplasmic membrane, physically interacts with and colocalizes with MmpL3 in growing cells, and is required for trehalose monomycolate (TMM) transport to the cell wall. In light of these findings, we propose MSMEG_0736/Rv0383c be named "TMM transport factor A", TtfA. The protein encoded by MSMEG_5308 also interacts with the MmpL3 complex but is nonessential for growth or TMM transport. However, MSMEG_5308 accumulates with inhibition of MmpL3-mediated TMM transport and stabilizes the MmpL3/TtfA complex, indicating that it may stabilize the transport system during stress. These studies identify two new components of the mycobacterial mycolate transport machinery, an emerging antibiotic target in M. tuberculosis IMPORTANCE The cell envelope of Mycobacterium tuberculosis, the bacterium that causes the disease tuberculosis, is a complex structure composed of abundant lipids and glycolipids, including the signature lipid of these bacteria, mycolic acids. In this study, we identified two new components of the transport machinery that constructs this complex cell wall. These two accessory proteins are in a complex with the MmpL3 transporter. One of these proteins, TtfA, is required for mycolic acid transport and cell viability, whereas the other stabilizes the MmpL3 complex. These studies identify two new components of the essential cell envelope biosynthetic machinery in mycobacteria.

KEYWORDS:

Mycobacterium; Mycobacterium tuberculosis; cell envelope; transporters

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