Type IV secretion systems (T4SSs)

Bacteria transport numerous substrates across cellular membranes via secretion systems that are essential for virulence and survival. Type IV secretion systems (T4SSs) are versatile, bacterial membrane-spanning apparatuses, composed of diverse structural units, which mediate both genetic exchange and the delivery of effector proteins to target eukaryotic cells. Hence, these secretory organelles play key roles in bacterial genome plasticity and pathogenesis [Cascales and Christie (2003) Nat Rev Microbiol; Fronzes, et al (2009) Nat Rev Microbiol]. Indeed, T4SSs have been directly implicated in the horizontal transfer of genes coding for virulence determinants, antibiotic resistance and other bacterial adaptation traits [Alvarez-Martinez, et al (2009) Microbiol Mol Biol Rev; Juhas, et al (2008) Cell Microbiol].

T4SSs have been classified into three subfamilies by function [Cascales and Christie (2003) Nat Rev Microbiol]. 'Conjugation associated' T4SSs mediate contact-dependent DNA transfe rfrom a donor bacterial cell into diverse bacterial species and even in selected instances into fungal, plant or human cells. Plasmid-encoded T4SSs have been initially classified into types F, P and I, corresponding to the plasmid incompatibility groups IncF, IncP and IncI, respectively, of the index members of each of these T4SS subtypes [Lawley, et al (2003) FEMS Microbiol Lett]. The conjugation apparatuses encoded by integrative and conjugative elements (ICEs) found in Gram-negative bacteria have also either been shown or are proposed to comprise T4SSs [Wozniak and Waldor (2010) Nat Rev Microbiol]. Further information on ICEs that carry T4SSs can be reviewed via our recently developed ICEberg database [Bi, et al (2012) Nucleic Acids Res]. ‘DNA uptake and release’ T4SSs function independently of contact with a target cell and instead promote genetic exchange by a different mechanism. Finally, ‘effector translocator’ T4SSs inject effectors into target eukaryotic cells during host–bacterium interaction processes to mediate bacterium-directed subversion of a myriad of host cell functions. For example, the Cag system encoded by a Helicobacter pylori pathogenicity island is strongly implicated in the pathogenesis of chronic gastritis, peptic ulcers and even gastric cancer [Tegtmeyer, et al (2011) FEBS J], while effectors secreted by the Legionella pneumophila Dot/Icm system trigger robust immune responses [Luo (2012) Cell Microbiol]. By contrast, the well studied Agrobacterium tumefaciens VirB/D system delivers both oncogenic DNA and proteins into plant cell [Cascales and Christie (2003) Nat Rev Microbiol].

Homologues of T4SSs are being identified in increasing numbers as the available bacterial genome sequence data expands exponentially [Guglielmini, et al (2011) PLoS Genet]. Prediction of T4SS effectors has also been facilitated by an expanded machine learning-based strategy [Burstein, et al (2009) PLoS Pathogens]. Furthermore, progress in elucidating the structural biology of T4SSs has allowed us to better understand the workings of this multiunit, mutlifunction machine [Fronzes, et al (2009) Nat Rev Microbiol].

SecReT4, a database of T4SSs

SecReT4 contains detailed DNA and protein information on all archived T4SSs, matching essential component parts and/or effector molecules, including unique identifiers, host species details, sequences, functions and hyperlink-paths to other public databases, such as NCBI, UniprotKB, PDB and KEGG. Users can create genetic maps of T4SSs, investigate gene loci of interest with the embedded graphic display, search for T4SSs by type, function or host organism. Users can also search a query sequence by BLAST or HMMER3 against SecReT4 to identify potential homologues of T4SS components or effectors and opt to submit newly identified entities into the growing database. The multiple sequence alignment tool MUSCLE and Jalview are also readily accessible to allow for user-directed analyses focused on diverse T4SS components, thus facilitating varied individualized directions of research. SecReT4 automates primer design for PCR amplification of sequences coding for conserved T4SS components. We also provide a web tool to identify T4SS components in user-supplied DNA sequences.

Ultimately, we envisage that SecReT4 will facilitate efficient investigation of large numbers of these systems, recognition of diverse patterns of sequence-, gene- and/or functional conservation, and an improved understanding of the biological roles and significance of these versatile molecular machines. We expect that SecReT4 will prove to be of major interest to a broad community of researchers.