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Chapter 28 : The Sec Pathways and Exportomes of

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Abstract:

Approximately 20% of bacterial proteins have functions outside the cytoplasm ( ). Consequently, all bacteria possess protein export pathways that transport proteins made in the cytoplasm beyond the cytoplasmic membrane. These exported proteins may remain in the bacterial cell envelope or be further secreted to the extracellular environment. Many exported proteins function in essential physiological processes. Additionally, in bacterial pathogens, many exported proteins have functions in virulence. Consequently, the pathways that export proteins are commonly essential and/or are important for pathogenesis. Across bacteria, including mycobacteria, there are conserved protein export pathways: the general secretion (Sec) and the twin-arginine translocation (Tat) pathways. Both Sec and Tat pathways are essential to the viability of and both also contribute to virulence (L. Rank and M. Braunstein, unpublished; ). In addition to these conserved pathways, bacterial pathogens commonly have specialized protein export systems that are important for pathogenesis due to their role in exporting virulence factors. Mycobacteria also have specialized protein export systems: the SecA2 export pathway and five ESX (type VII) pathways. In this article, we focus on the conserved Sec pathway and the specialized SecA2 pathway, review what is known about their respective exportomes, and discuss their importance during replication and persistence within the host.

Citation: Miller B, Zulauf K, Braunstein M. 2017. The Sec Pathways and Exportomes of , p 607-625. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0013-2016
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Image of Figure 1
Figure 1

Models of SecA1 and SecA2 export in . SecA1 uses ATP hydrolysis to export preproteins through the SecYEG channel in an unfolded, export-competent state. Sec signal peptides (black rectangle) target preproteins (blue ribbon) for export through SecYEG and are then cleaved by a signal peptidase (SP). SecA2 also uses the SecYEG channel and possibly SecA1 to export its own subset of preproteins (green ribbon). The signal peptide (black rectangle) is indistinguishable from canonical Sec signal peptides. Instead, the mature domain’s propensity for cytoplasmic folding is predicted to confer specificity for SecA2.

Citation: Miller B, Zulauf K, Braunstein M. 2017. The Sec Pathways and Exportomes of , p 607-625. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0013-2016
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Image of Figure 2
Figure 2

Solute-binding proteins and Mce proteins are exported by the SecA2 pathway. Two classes of SecA2-dependent substrates are SBPs and Mce proteins. Both SBPs and Mce proteins are involved in solute acquisition. In the case of SBPs this involves import of a solute through an ABC transporter permease using energy provided by ATP hydrolysis. Mce transporters are thought to function in a similar manner as ABC transporters to import a lipid substrate through a YrbE permease in an ATP-dependent manner. Although the diagram of an Mce transporter is speculative, the similarities between these two systems are compelling.

Citation: Miller B, Zulauf K, Braunstein M. 2017. The Sec Pathways and Exportomes of , p 607-625. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0013-2016
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Figure 3

Multiple components of Mce transporters are reduced in the cell wall of the Δ mutant. The genome contains four loci encoding putative lipid transporters. The genomic regions encoding Mce1, Mce3, and Mce4 transporters are shown with open reading frames colored for Mce proteins that are reduced in quantitative mass spectrometry studies of the () and () Δ mutant cell wall or cell envelope fractions ( ). In dark blue and/or green are genes for proteins that are significantly reduced ( < 0.01 for and < 0.05 for ) in the Δ mutant; in light blue are genes for Mce proteins that are reduced in the Δ mutant but did not reach statistical significance.

Citation: Miller B, Zulauf K, Braunstein M. 2017. The Sec Pathways and Exportomes of , p 607-625. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0013-2016
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Figure 4

SecA2 export is required for virulence. The SecA2 pathway combats multiple host immune mechanisms of macrophages. SecA2 export of PknG in addition to other unknown effectors prevents phagosome acidification and fusion with degradative lysosomes. Export of SodA and KatG by SecA2 combats harmful reactive oxygen radicals and limits apoptosis. SecA2 also inhibits signaling through MyD88 by unknown mechanisms, resulting in lower levels of the proinflammatory cytokines interleukin-6 and tumor necrosis factor alpha along with nitric oxide. Additionally, SecA2 reduces gamma interferon-induced MHC II levels, which could impact antigen presentation to CD4+ T cells.

Citation: Miller B, Zulauf K, Braunstein M. 2017. The Sec Pathways and Exportomes of , p 607-625. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0013-2016
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