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Type VII secretion systems: structure, functions and transport models. ​

Literature Information ​

DOI10.1038/s41579-021-00560-5
PMID34040228
JournalNature reviews. Microbiology
Impact Factor103.3
JCR QuartileQ1
Publication Year2021
Times Cited47
KeywordsType VII secretion systems, effector proteins, molecular biology, Mycobacterium tuberculosis, transport models
Literature TypeJournal Article, Research Support, Non-U.S. Gov't, Review
ISSN1740-1526
Pages567-584
Issue19(9)
AuthorsAngel Rivera-Calzada, Nikolaos Famelis, Oscar Llorca, Sebastian Geibel

TL;DR ​

This review discusses the critical role of Type VII secretion systems (T7SSs) in both pathogenic and non-pathogenic mycobacteria, particularly focusing on their function in Mycobacterium tuberculosis, which causes significant mortality worldwide. Advances in structural and molecular biology have unveiled the complex interactions within T7SSs, offering insights into their effector protein transport mechanisms and potential new strategies for targeting this deadly pathogen.

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Type VII secretion systems · effector proteins · molecular biology · Mycobacterium tuberculosis · 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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Primary Questions Addressed ​

  1. What are the specific roles of different paralogous T7SSs in the survival of pathogenic mycobacteria within the host?
  2. How do recent structural characterizations of T7SSs enhance our understanding of their function in immune evasion?
  3. What are the potential therapeutic implications of targeting the T7SSs in Mycobacterium tuberculosis?
  4. In what ways do the effector proteins secreted by T7SSs interact with host cellular mechanisms?
  5. How does the regulation of T7SSs vary between non-pathogenic and pathogenic mycobacteria, and what are the implications for treatment strategies?

Key Findings ​

Key Insights ​

  1. Research Background and Purpose: The primary focus of this research is the Type VII secretion systems (T7SSs), which play a critical role in the secretion of effector proteins in both non-pathogenic and pathogenic mycobacteria, specifically Mycobacterium tuberculosis, the leading cause of tuberculosis globally. Given that tuberculosis results in approximately 1.4 million deaths each year, understanding the mechanisms by which T7SSs facilitate the survival and immune evasion of pathogenic mycobacteria is essential for developing effective therapeutic interventions.

  2. Main Methods and Findings: The review compiles recent advancements in the structural characterization of T7SSs, emphasizing the intricate network of interactions among the conserved components within the plasma membrane of mycobacteria. Although the precise mechanism through which the effector proteins traverse the outer membrane of the diderm mycobacterial cell envelope remains unclear, the emerging structural data, combined with progress in molecular biology and the regulatory dynamics of T7SSs, provide significant insights into the T7SS machinery. The authors discuss various transport models that have emerged from these findings, which could explain how these systems operate at a molecular level.

  3. Core Conclusions: The findings suggest that the T7SSs are not merely passive structures but are actively involved in the complex interactions required for mycobacterial pathogenesis. The detailed understanding of T7SSs' structure and function points to the existence of sophisticated transport mechanisms that enable the export of effector proteins essential for the bacteria’s survival and virulence. The insights gained from this research enhance our comprehension of how pathogenic mycobacteria manipulate host defenses, thereby contributing to the persistence and spread of tuberculosis.

  4. Research Significance and Impact: The implications of this research are profound, as understanding the T7SSs and their operational mechanisms could pave the way for novel therapeutic strategies against tuberculosis. By identifying the critical components and processes involved in T7SS function, researchers may develop targeted interventions that disrupt these pathways, thereby enhancing the effectiveness of current therapies or leading to the creation of new ones. Ultimately, this research could significantly impact global public health by providing tools to combat one of the world’s deadliest infectious diseases.

References ​

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Literatures Citing This Work ​

  1. A Small Protein but with Diverse Roles: A Review of EsxA in Mycobacterium-Host Interaction. - Yanqing Bao;Lin Wang;Jianjun Sun - Cells (2021)
  2. Secretion Systems in Gram-Negative Bacterial Fish Pathogens. - Sophanit Mekasha;Dirk Linke - Frontiers in microbiology (2021)
  3. A Comparative Analysis of Weizmannia coagulans Genomes Unravels the Genetic Potential for Biotechnological Applications. - Martina Aulitto;Laura Martinez-Alvarez;Gabriella Fiorentino;Danila Limauro;Xu Peng;Patrizia Contursi - International journal of molecular sciences (2022)
  4. Peptidomimetics as Potential Anti-Virulence Drugs Against Resistant Bacterial Pathogens. - Osmel Fleitas Martínez;Harry Morales Duque;Octávio Luiz Franco - Frontiers in microbiology (2022)
  5. Design Principles of the Rotary Type 9 Secretion System. - Abhishek Trivedi;Jitendrapuri Gosai;Daisuke Nakane;Abhishek Shrivastava - Frontiers in microbiology (2022)
  6. Comparative Genomic Analysis of Type VII Secretion System in Streptococcus agalactiae Indicates Its Possible Sequence Type-Dependent Diversity. - Kaixin Zhou;Lianyan Xie;Xiaogang Xu;Jingyong Sun - Frontiers in cellular and infection microbiology (2022)
  7. Proteo-genetic analysis reveals clear hierarchy of ESX-1 secretion in Mycobacterium marinum. - Rachel M Cronin;Micah J Ferrell;Clare W Cahir;Matthew M Champion;Patricia A Champion - Proceedings of the National Academy of Sciences of the United States of America (2022)
  8. Are Virulence and Antibiotic Resistance Genes Linked? A Comprehensive Analysis of Bacterial Chromosomes and Plasmids. - Helena Darmancier;Célia P F Domingues;João S Rebelo;Ana Amaro;Francisco Dionísio;Joël Pothier;Octávio Serra;Teresa Nogueira - Antibiotics (Basel, Switzerland) (2022)
  9. Bacterial secretion systems: Networks of pathogenic regulation and adaptation in mycobacteria and beyond. - Kathleen R Nicholson;Patricia A Champion - PLoS pathogens (2022)
  10. Immune evasion and provocation by Mycobacterium tuberculosis. - Pallavi Chandra;Steven J Grigsby;Jennifer A Philips - Nature reviews. Microbiology (2022)

... (37 more literatures)

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