Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Jul;7(4):10.1128/microbiolspec.gpp3-0043-2018.
doi: 10.1128/microbiolspec.GPP3-0043-2018.

Protein Export into and across the Atypical Diderm Cell Envelope of Mycobacteria

Vincent J C van Winden  1 , Edith N G Houben  2 , Miriam Braunstein  3
Affiliations
Review

Protein Export into and across the Atypical Diderm Cell Envelope of Mycobacteria

Vincent J C van Winden et al. Microbiol Spectr. 2019 Jul.

Abstract

Mycobacteria, including the infamous pathogen Mycobacterium tuberculosis, are high-GC Gram-positive bacteria with a distinctive cell envelope. Although there is a typical inner membrane, the mycobacterial cell envelope is unusual in having its peptidoglycan layer connected to a polymer of arabinogalactan, which in turn is covalently attached to long-chain mycolic acids that help form a highly impermeable mycobacterial outer membrane. This complex double-membrane, or diderm, cell envelope imparts mycobacteria with unique requirements for protein export into and across the cell envelope for secretion into the extracellular environment. In this article, we review the four protein export pathways known to exist in mycobacteria: two conserved systems that exist in all types of bacteria (the Sec and Tat pathways) and two specialized systems that exist in mycobacteria, corynebacteria, and a subset of low-GC Gram-positive bacteria (the SecA2 and type VII secretion pathways). We describe the progress made over the past 15 years in understanding each of these mycobacterial export pathways, and we highlight the need for research to understand the specific steps of protein export across the mycobacterial outer membrane.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1
Model of the mycobacterial cell envelope and export systems. Although the mycobacterial cell envelope contains a traditional cytosolic (inner) membrane, the peptidoglycan layer is covalently linked to an arabinogalactan layer consisting of arabinose and galactose, which in turn is covalently linked to mycolic acids. These unusually long fatty acids (up to 90 carbon atoms) are one of the main components of the outer membrane, which also contains noncovalently bound (free) lipids. The final layer of the cell envelope is the capsule, mainly consisting of polysaccharides and proteins. The cell envelope is highly impermeable and unique to other Gram-positive bacteria. To export proteins into and across the cell envelope, mycobacteria have four systems, Sec, SecA2, Tat, and type VII secretion (T7S). The Sec pathway exports unfolded proteins across the inner membrane, and the substrates bind to an ATPase, SecA1, which targets the substrates to the translocation channel consisting of SecYEG and provides energy for translocation. The additional membrane components SecD, SecF, and YajC increase the efficiency of export. Upon translocation across the inner membrane, the N-terminal signal peptide (depicted in gray) is removed by a signal peptidase (SP). Less is known about the SecA2 pathway. Substrates are dependent on the ATPase SecA2; however, studies show that they also utilize the SecYEG channel and possibly SecA1, as well. The list of SecA2-dependent exported proteins includes examples with and without a signal peptide. The third export system, the Tat pathway, exports folded proteins. The Tat substrates, containing an N-terminal signal peptide, with a pair of arginine residues, is targeted to the membrane components TatBC, which then recruit homo-oligomers of TatA for subsequent transportation across the membrane. Similar to Sec, the signal peptide is removed by a signal peptidase. The T7S system consists of five conserved membrane components, of which EccBCDE form the secretion complex. EccC is the ATPase, providing the required energy for the secretion process. Although the mycosin protease (MycP) is not an integral component of the secretion complex, it associates with the complex and is essential for successful secretion. The substrates (Esx and PE-PPE) are secreted as heterodimers and are targeted to the secretion complex by a conserved secretion signal that includes a YxxxD/E motif (depicted in red), whereas the cytosolic chaperone EspG is required for directing the PE-PPE pairs to their specific T7S. The role of the second conserved cytosolic component, EccA, remains uncertain. It is currently unknown how Sec, SecA2, Tat, and T7S substrates are secreted across the outer membrane into the capsular layer or culture supernatant. IM, inner membrane; PG, peptidoglycan layer; AG, arabinogalactan layer; MA, mycolic acids; NL, noncovalently bound lipids; OM, outer membrane.
FIGURE 2
FIGURE 2
Roles of ESX systems in DNA transfer, and cell physiology and nutrient uptake. (A) The pRAW plasmid-encoded ESX-P1 system, present in certain strains of M. marinum, is involved in DNA conjugation, allowing the transfer of the plasmid to other slow-growing mycobacteria (161). Similar plasmids are found in other mycobacteria, and they have been linked to the evolution and distribution of esx gene clusters within mycobacteria (162, 256). In addition, the ESX-1 and ESX-4 systems of M. smegmatis are involved in distributive conjugal transfer, allowing the horizontal gene transfer of random large genomic fragments (143, 159). (B) A second major role of the ESX-systems is in cell physiology. While the ESX-1 system has been linked to the integrity of the cell envelope and the biosynthesis of mycolic acids (196, 210, 264), the ESX-3 and ESX-5 systems are involved in the uptake of metabolites and nutrients, respectively. The ESX-3 system and two of its substrate pairs (EsxG-EsxH and PE5-PPE4) have been specifically linked to the uptake of iron and zinc (144, 145, 147), while the ESX-5 system has been linked to the utilization of fatty acids and possibly other nutrients (149) Finally, the ESX-5 system secretes a substrate (PPE10) that is required for the integrity of the capsular layer (199). IM, inner membrane; OM, outer membrane.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. WHO. 2018. Global tuberculosis report. World Health Organization, Geneva, Switzerland. [PubMed]
    1. Roy A, Eisenhut M, Harris RJ, Rodrigues LC, Sridhar S, Habermann S, Snell L, Mangtani P, Adetifa I, Lalvani A, Abubakar I. 2014. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis. BMJ 349:g4643 10.1136/bmj.g4643. [PubMed] - DOI - PMC - PubMed
    1. Brennan PJ, Nikaido H. 1995. The envelope of mycobacteria. Annu Rev Biochem 64:29–63 10.1146/annurev.bi.64.070195.000333. - DOI - PubMed
    1. Houben ENG, Korotkov KV, Bitter W. 2014. Take five: type VII secretion systems of mycobacteria. Biochim Biophys Acta 1843:1707–1716 10.1016/j.bbamcr.2013.11.003. [PubMed] - DOI - PubMed
    1. Barry CE III, Lee RE, Mdluli K, Sampson AE, Schroeder BG, Slayden RA, Yuan Y. 1998. Mycolic acids: structure, biosynthesis and physiological functions. Prog Lipid Res 37:143–179 10.1016/S0163-7827(98)00008-3. - DOI - PubMed

Publication types

Substances

LinkOut - more resources