Type IV secretion: intercellular transfer of macromolecules by systems ancestrally related to conjugation machines

Abstract

Bacterial conjugation systems are highly promiscuous macromolecular transfer systems that impact human health significantly. In clinical settings, conjugation is exceptionally problematic, leading to the rapid dissemination of antibiotic resistance genes and other virulence traits among bacterial populations. Recent work has shown that several pathogens of plants and mammals - Agrobacterium tumefaciens, Bordetella pertussis, Helicobacter pylori and Legionella pneumophila - have evolved secretion pathways ancestrally related to conjugation systems for the purpose of delivering effector molecules to eukaryotic target cells. Each of these systems exports distinct DNA or protein substrates to effect a myriad of changes in host cell physiology during infection. Collectively, secretion pathways ancestrally related to bacterial conjugation systems are now referred to as the type IV secretion family. The list of putative type IV family members is increasing rapidly, suggesting that macromolecular transfer by these systems is a widespread phenomenon in nature.

Fig. 1

The type IV secretion family includes conjugation machines and ancestrally related systems that deliver effector molecules to eukaryotic cells.

Fig. 2

The type IV systems known or postulated to translocate macromolecular substrates intercellularly. The A. tumefaciens virB gene products shown across the top assemble as the T-DNA transfer system. The next three groups of type IV systems, separated by dashed lines, are composed of homologues of some or all of the VirB proteins. The top group corresponds to systems shown to transfer DNA between bacteria, the B. pertussis and H. pylori systems deliver known substrates (PT and CagA respectively) to mammalian cells, and the third group corresponds to systems whose substrates are presently unknown but are postulated to be effector proteins. The symbol (?) denotes the absence of sequence information in the database for other virB genes in these bacteria. The L. pneumophila dot/icm gene products shown across the bottom are homologues of the Shigella flexneri Collb-P9 (Incl) transfer proteins. This system can conjugally transfer DNA, but its proposed role in virulence is to export effector proteins.

Fig. 3

The known type IV systems differ with respect to the route of substrate translocation. The A. tumefaciens T-DNA transfer system and the H. pylori CagA system are thought to export substrates in one step across the membrane directly to the eukaryotic cytosol. The B. pertussis Ptl system is thought to export PT in two steps across the cell envelope to the extracellular milieu. Secreted holotoxin then binds to the mammalian cell membrane. See text for additional details.

Fig. 4

Crystal structure of H. pylori HP0525 bound to ADP. Each subunit is in ribbon representation colour-coded differently. ADP is in ball-and-stick representation colour-coded in magenta. This figure was kindly provided by G. Waksman (see Yeo et al., 2000).