Two Accessory Proteins Govern MmpL3 Mycolic Acid Transport in Mycobacteria

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...

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Autores principales:	Allison Fay, Nadine Czudnochowski, Jeremy M. Rock, Jeffrey R. Johnson, Nevan J. Krogan, Oren Rosenberg, Michael S. Glickman
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Mycobacterium Mycobacterium tuberculosis cell envelope transporters Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0c61a1c4c8a74e1dae2c681040bf409e
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spelling	oai:doaj.org-article:0c61a1c4c8a74e1dae2c681040bf409e2021-11-15T15:55:24ZTwo Accessory Proteins Govern MmpL3 Mycolic Acid Transport in Mycobacteria10.1128/mBio.00850-192150-7511https://doaj.org/article/0c61a1c4c8a74e1dae2c681040bf409e2019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00850-19https://doaj.org/toc/2150-7511ABSTRACT 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.Allison FayNadine CzudnochowskiJeremy M. RockJeffrey R. JohnsonNevan J. KroganOren RosenbergMichael S. GlickmanAmerican Society for MicrobiologyarticleMycobacteriumMycobacterium tuberculosiscell envelopetransportersMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mycobacterium Mycobacterium tuberculosis cell envelope transporters Microbiology QR1-502
spellingShingle	Mycobacterium Mycobacterium tuberculosis cell envelope transporters Microbiology QR1-502 Allison Fay Nadine Czudnochowski Jeremy M. Rock Jeffrey R. Johnson Nevan J. Krogan Oren Rosenberg Michael S. Glickman Two Accessory Proteins Govern MmpL3 Mycolic Acid Transport in Mycobacteria
description	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.
format	article
author	Allison Fay Nadine Czudnochowski Jeremy M. Rock Jeffrey R. Johnson Nevan J. Krogan Oren Rosenberg Michael S. Glickman
author_facet	Allison Fay Nadine Czudnochowski Jeremy M. Rock Jeffrey R. Johnson Nevan J. Krogan Oren Rosenberg Michael S. Glickman
author_sort	Allison Fay
title	Two Accessory Proteins Govern MmpL3 Mycolic Acid Transport in Mycobacteria
title_short	Two Accessory Proteins Govern MmpL3 Mycolic Acid Transport in Mycobacteria
title_full	Two Accessory Proteins Govern MmpL3 Mycolic Acid Transport in Mycobacteria
title_fullStr	Two Accessory Proteins Govern MmpL3 Mycolic Acid Transport in Mycobacteria
title_full_unstemmed	Two Accessory Proteins Govern MmpL3 Mycolic Acid Transport in Mycobacteria
title_sort	two accessory proteins govern mmpl3 mycolic acid transport in mycobacteria
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/0c61a1c4c8a74e1dae2c681040bf409e
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_version_	1718427196626829312

Two Accessory Proteins Govern MmpL3 Mycolic Acid Transport in Mycobacteria

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