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Type VII secretion systems: structure, functions and transport models

Abstract

Type VII secretion systems (T7SSs) have a key role in the secretion of effector proteins in non-pathogenic mycobacteria and pathogenic mycobacteria such as Mycobacterium tuberculosis, the main causative agent of tuberculosis. Tuberculosis-causing mycobacteria, still accounting for 1.4 million deaths annually, rely on paralogous T7SSs to survive in the host and efficiently evade its immune response. Although it is still unknown how effector proteins of T7SSs cross the outer membrane of the diderm mycobacterial cell envelope, recent advances in the structural characterization of these secretion systems have revealed the intricate network of interactions of conserved components in the plasma membrane. This structural information, added to recent advances in the molecular biology and regulation of mycobacterial T7SSs as well as progress in our understanding of their secreted effector proteins, is shedding light on the inner working of the T7SS machinery. In this Review, we highlight the implications of these studies and the derived transport models, which provide new scenarios for targeting the deathly human pathogen M. tuberculosis.

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Fig. 1: Genetic and functional organization of mycobacterial type VII secretion systems.
Fig. 2: Structural model of the membrane-embedded type VII secretion system core complex.
Fig. 3: Organization of T7SSb and structural comparison with mycobacterial T7SSs.
Fig. 4: Transport models of mycobacterial type VII secretion systems.
Fig. 5: Roles of mycobacterial type VII secretion systems in the pathogenesis of tuberculosis.

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Acknowledgements

This work was funded by the Elite Network of Bavaria (N-BM-2013-246 to S.G.), bayresq.net (S.G.), grant SAF2017-82632-P to O.L. from the Spanish Ministry of Science, Innovation and Universities (MCIU/AEI), co-funded by the European Regional Development Fund, the support of the Spanish National Institute of Health Carlos III provided to CNIO, and grants Y2018/BIO4747 and P2018/NMT4443 from the Autonomous Region of Madrid and co-funded by the European Social Fund and the European Regional Development Fund to the activities of the group directed by O.L.

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A.R.-C. and S.G. researched data for the article. A.R.-C., N.F. and S.G. contributed substantially to discussion of the content. A.R.-C., O.L. and S.G. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Angel Rivera-Calzada or Sebastian Geibel.

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Glossary

Arabinogalactan layer

An essential constituent of the mycobacterial cell wall. Peptidoglycan is covalently attached to the heteropolysaccharide arabinogalactan, which is in turn linked to the mycolic acid layer.

Capsule

The mycobacterial capsule is the outermost layer of the bacterial cell and consists mainly of a glycogen-like α-glucan with lower amounts of arabinomannan and mannan, proteins and lipids. This layer mediates key interactions with host cells during initial stages of infection and favours bacterial survival.

Diderm

A term to describe the presence of an inner membrane and an outer membrane in the cell envelope such as in Gram-negative bacteria and mycobacteria.

3D variability analysis

A tool to analyse the heterogeneity in single-particle cryogenic electron microscopy data sets revealing the different 3D conformations that appear in the sample. It can be used to characterize the conformational space and the amount of flexibility present in a molecule.

Pyroptosis

Type of programmed cell death different from apoptosis and necroptosis that promotes lytic cell death, causing the release of the cellular content and inducing inflammatory responses in the organism.

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Rivera-Calzada, A., Famelis, N., Llorca, O. et al. Type VII secretion systems: structure, functions and transport models. Nat Rev Microbiol (2021). https://doi.org/10.1038/s41579-021-00560-5

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