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  • Review Article
  • Published:

The versatile bacterial type IV secretion systems

Nature Reviews Microbiology volume 1, pages 137–149 (2003)Cite this article

Key Points

  • Bacterial type IV secretion (T4S) systems are ancestrally related to conjugation systems. Present-day T4S systems can be subclassified into three groups: conjugation systems mediating the transfer of DNA and protein substrates through formation of stable mating junctions with recipient cells; DNA-uptake and -release systems that exchange DNA with the extracellular milieu; and effector translocator systems that deliver DNA and protein effector molecules to eukaryotic cells during the course of infection.

  • The conjugation systems of Gram-negative bacteria are composed of the coupling protein homomultimer and two substructures encoded by the mating-pair-formation (Mpf) proteins, a protein complex spanning the cell envelope and the conjugative pilus (T-pilus).

  • At the present time, investigators have identified the effector molecules of T4S systems for four pathogens: Agrobacterium tumefaciens, the causative agent of crown gall disease in plants; Helicobacter pylori, the causative agent of gastritis, peptic ulcers and gastric carcinomas in humans; Bordetella pertussis, the causative agent of whooping cough in humans; and Legionella pneumophila, the causative agent of Legionnaire's disease in humans.

  • T4S system effector translocation alters a wide range of cellular processes to aid the infection process. For example, Agrobacterium tumefaciens delivers oncogenic T-DNA and protein effectors (VirE2, VirE3 and VirF) that interact with plant cellular factors to ensure delivery of the T-DNA to the nucleus and its integration into the plant genome.

  • Helicobacter pylori uses the Cag T4S system to deliver CagA to mammalian cells where it is tyrosine phosphorylated by c-Src kinase. A complex network of interactions between CagAP-Tyr and cellular factors (for example, c-Src, SHP-2, c-MET) and between non-phosphorylated CagA (Grb2, JAM, Z0-1) alters signalling pathways, ultimately triggering cellular proliferation and differentiation and the onset of cancer.

  • The Bordetella pertussis Ptl system delivers its effector, the multisubunit pertussis toxin, to the extracellular milieu where, on contact with the mammalian cell membrane, the A subunit is internalized and exerts its effects by uncoupling G proteins from their receptors.

  • In striking contrast to the other systems described in the review, the intracellular pathogen L. pneumophila uses the Dot/Icm T4S system to inject effectors (DotA, LidA, RalF) into the phagosome to control biogenesis of the replicative vacuoule and to modulate the activities of host factors involved in vesicle traffic.

Abstract

Bacteria use type IV secretion systems for two fundamental objectives related to pathogenesis — genetic exchange and the delivery of effector molecules to eukaryotic target cells. Whereas gene acquisition is an important adaptive mechanism that enables pathogens to cope with a changing environment during invasion of the host, interactions between effector and host molecules can suppress defence mechanisms, facilitate intracellular growth and even induce the synthesis of nutrients that are beneficial to bacterial colonization. Rapid progress has been made towards defining the structures and functions of type IV secretion machines, identifying the effector molecules, and elucidating the mechanisms by which the translocated effectors subvert eukaryotic cellular processes during infection.

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Figure 1: Schematic representation of the different type-IV-dependent mechanisms.
Figure 2: Topologies of the VirB/D4 subunits of the A. tumefaciens type IV secretion (T4S) system.
Figure 3: Models of type IV secretion (T4S) system-mediated substrate translocation.
Figure 4: Schematic representation of the cellular consequences of type IV secretion (T4S) system effector translocation.

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Acknowledgements

We dedicate this review to Brian Wilkins in loving memory. We apologize for any omissions in citation of primary reports owing to space limitations. We thank members of the laboratory for helpful comments and critical appraisals of this manuscript. We also gratefully acknowledge the National Institutes of Health for supporting our studies of the Agrobacterium VirB/D4 T4S system.

Author information

Authors and Affiliations

  1. Department of Microbiology and Molecular Genetics, The University of Texas-Houston Medical School, Houston, 77030, Texas, USA

    Eric Cascales & Peter J. Christie

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  1. Eric Cascales
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Correspondence to Peter J. Christie.

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DATABASES

Entrez

HP0527

HP0528

HP0532

Protein Data Bank

HP0525

TrwB

SwissProt

ARF1

JAM

VirB1

VirB11

VirD4

FURTHER INFORMATION

Peter J. Christie's laboratory

World Health Organization

Glossary

TYPE IV SECRETION (T4S) APPARATUS OR SYSTEM

A bacterial organelle that is ancestrally related to a conjugation machine that translocates DNA or protein substrates across the cell envelope, often for purposes associated with pathogenesis. Other bacterial translocation systems include the type II secretion (T2S) machines that deliver protein substrates across the outer membrane and the type III secretion (T3S) machines that translocate effectors in one step across the cell envelope through a structure that is ancestrally related to the bacterial flagellum. Like the T4S systems, the T3S systems elaborate syringe- or pilus-like surface organelles and deliver effector proteins to plant and mammalian cells during infection.

CONJUGATION

A mechanism for transfer of a DNA substrate from a bacterial donor cell to a recipient cell by direct cell-to-cell contact.

PILUS

A filamentous organelle that extends from the surface of the bacterial cell. Composed of pilin subunits, these structures mediate attachment to target cells or inert matter. They might also participate directly in the delivery of secretion substrates to target cells.

COMPETENCE

The ability of a bacterial cell to import exogenous DNA and stably incorporate it into the bacterial genome.

PERIPLASM

An aqueous compartment between the inner and outer membranes of Gram-negative bacteria.

CHAPERONE

A protein or protein complex that participates in folding or unfolding of protein substrates. Secretion chaperones prevent their substrates from aggregating or interacting prematurely with other substrates or cellular factors. They might also mediate the delivery of substrates to a secretory apparatus.

SECRETION SIGNAL

A motif that confers recognition of a protein that is destined for export by a cognate secretory apparatus.

GENERAL SECRETORY PATHWAY

(GSP). The main pathway used for delivery of protein substrates into or across the bacterial inner membrane.

INTERLEUKIN-8

(IL-8). A peptide that is produced by epithelial cells and is an indicator of infection. IL-8 secretion is induced by pathogens preceding clinical complications.

TRANSGLYCOSYLASE

A protein, the enzymatic activity of which degrades peptidoglycan. These proteins participate in assembly of supramolecular transenvelope structures by 'punching' holes in the peptidoglycan.

PEPTIDOGLYCAN

A shape-determining polymer that is present within the periplasm of Gram-negative bacteria.

SECRETIN

A protein that forms oligomeric pores to allow the passage of macromolecular substrates across the outer membrane.

KARYOPHERIN

These proteins have a central role in nuclear import processes, mediating substrate recognition and release at the nuclear-pore complex by GTP-hydrolysis-dependent reactions.

CORTACTIN

Cortactin is an actin-binding protein, regulated by the membrane-associated c-Src kinase. Cortactin transduces signals from the cell surface to the cytoskeleton.

ACTIN

A eukaryotic protein that polymerizes to form microfilaments. Microfilaments have a dual role, acting as a passive structural complex that maintains cell shape and anchors cytoskeletal proteins, and an active function for the transport of vesicles and organelles that can result in cell movement.

APICAL JUNCTION

Apical junctions consist of protein complexes that join the actin cytoskeleton to the apical pole of epithelial cells. Adherent junctions have pivotal roles in cell organization by mediating cell adhesion and signalling.

ADP RIBOSYLATION FACTOR

(ARF). The ADP-ribosylation factor family of small GTP-binding proteins is involved in the regulation of membrane traffic (vesicular transport) and in the control of the actin cytoskeleton.

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Cascales, E., Christie, P. The versatile bacterial type IV secretion systems. Nat Rev Microbiol 1, 137–149 (2003). https://doi.org/10.1038/nrmicro753

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