T4SSs are versatile apparatuses that can transport both proteins and DNA. Cascales and Christie [Cascales and Christie (2003) Nat Rev Microbiol] have summarrized T4SSs into three subfamilies by function including 'conjugation', 'DNA uptake and release', as well as 'effector translocator' systems. Hence, these secretory organelles play key roles in bacterial genome plasticity and pathogenesis.

1. 'Conjugation' associated T4SSs mediate contact-dependent DNA transfer from a donor bacterial cell into diverse bacterial species and even in selected instances into fungal, plant or human cells [Bates, et al (1998) J Bacteriol; Zhu, et al (2000) J Bacteriol; Waters (2001) Nat Genet]. T4SSs are essential for plasmid conjugation [Smillie, et al (2010) Microbiol Mol Biol Rev]. Besides, 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].

2. 'DNA uptake and release' T4SSs function independently of contact with a target cell and instead promote genetic exchange by a different mechanism. The Helicobacter pylori ComB system contributes to natural competence of hosts [Stingl, et al (2010) Proc Natl Acad Sci U S A], while the Neisseria gonorrhoeae Tra_F system is a DNA-release system [Hamilton and Dillard (2006) Mol Microbiol].

3. '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 [Christie (2004) Biochim Biophys Acta].T4SSs usually deliver their substrates through direct contact with the eukaryotic target cell. But Bordetella pertussis uses a T4SS to deliver its toxin substrate to the extracellular milieu [Dehio (2008) Cell Microbiol].

Recently, the T4SS was found to inject the effector into target bacterial cells and kill them. For example, Xanthomonas citri employs a T4SS and its cognate effector XAC2609 to kill competing bacteria in the close vicinity. The effector XAC2609 bears the C-terminal translocation signals, whose bacteriolytic activities degrade peptidoglycan in target cells, but in the donor cell can be neutralized by the synthesis of cognate immunity protein XAC2610 [Souza, et al (2015) Nat Commun.].

4. Some T4SSs participate in virulence via other ways. Such as the Trw system of Bartonella henselae str. Houston-1, which mediates host-specific adhesion to erythrocytes [Vayssier-Taussat, et al (2010) PLoS Pathog]