Chapter 13 : Type VII Secretion: A Highly Versatile Secretion System

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Bacterial secretion systems were initially studied in the Gram-negative bacterium K-12. When researchers started to explore protein secretion in different Gram-negative bacteria and especially in bacterial pathogens, it was clear that K-12 was not able to present us with a complete picture of protein secretion systems. Type II, type III, and type IV secretion systems were quickly discovered and revolutionized host-pathogen interaction studies. Gram-negative bacteria need these specialized secretion systems to transport proteins across two membranes (also called a diderm cell envelope). The presence of this complex cell envelope not only means that two membranes have to be crossed, but an additional problem is that there is no energy source at the outer membrane. This means that alternative mechanisms for protein transport need to be present, such as coupling the energy of the inner membrane to protein transport across the outer membrane or crossing the entire cell envelope in a single step. Although the discovery of different secretion systems in Gram-negative bacteria was a major breakthrough, the downside has been that secretion systems in other bacteria have been neglected. It was generally thought that secretion in other bacteria, which are generally monoderm, would completely depend on the universal Sec or Tat system. Only in recent years has this idea begun shifting, and again it started by studying pathogens, i.e., the pathogenic mycobacteria.

Citation: Ates L, Houben E, Bitter W. 2016. Type VII Secretion: A Highly Versatile Secretion System, p 357-384. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed),

Virulence Mechanisms of Bacterial Pathogens, Fifth Edition

. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.VMBF-0011-2015
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Image of Figure 1
Figure 1

Genetic loci of different T7S (and T7S-like) systems. Depicted are the T7S loci, , , and of H37Rv ( ), as well the T7S-like systems of (strain USA300, annotation based on Anderson et al. [ ]) and subsp. (strain 168, annotation based on Huppert et al. [ ]). Color coding represents conserved T7S membrane components (dark blue), (putative) substrates of the systems (green), cytosolic chaperones (yellow), and -specific T7S-like membrane components (light blue).

Citation: Ates L, Houben E, Bitter W. 2016. Type VII Secretion: A Highly Versatile Secretion System, p 357-384. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed),

Virulence Mechanisms of Bacterial Pathogens, Fifth Edition

. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.VMBF-0011-2015
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Image of Figure 2
Figure 2

Model for T7S in mycobacteria. The conserved membrane components (blue) form a complex in which the EccC homolog is the ATPase possibly providing energy for the secretion process. The mycosin (MycP) is not part of the core complex but is essential for successful secretion. The T7S substrates (green) are secreted dependently on the conserved signals YxxxD/E and WxG (red). Secretion of PE-PPE dimers is dependent on the cytosolic chaperones EspG and EccA (yellow). While EspG binds to the substrate pair in the cytosol, EccA might be involved in releasing this chaperone from the PE-PPE dimer upon contact with the membrane complex. In contrast, Esx proteins are not recognized by EspG, and their dependence on the cytosolic chaperones might be indirect due to interdependence of Esx and PE-PPE for secretion. The EspB monomer has a similar fold to PE-PPE dimers and contains the putative secretion signal. Upon translocation, EspB is processed and forms a heptamer with a barrel-like structure. Whether PE-PPE dimers adopt a similar quaternary structure is yet unknown. Secreted substrates can localize to the culture supernatant or remain attached in the capsular layer. Whether the secretion process is a one- or two-step process is not known, so a putative outer membrane component (gray) is indicated by a question mark.

Citation: Ates L, Houben E, Bitter W. 2016. Type VII Secretion: A Highly Versatile Secretion System, p 357-384. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed),

Virulence Mechanisms of Bacterial Pathogens, Fifth Edition

. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.VMBF-0011-2015
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Image of Figure 3
Figure 3

Crystal structures of T7S substrates. Structure of the heterodimer EsxB (dark blue) and EsxA (light blue) of (3FAV). The two proteins form a four-helix bundle. The Tyr of the YxxxD motif and the Gly and Trp residues of the WxG motif that are postulated to together constitute the T7S signal are shown in red ( ). The EsxA protein of forms a homodimer that results in two putative secretion signals (VxxxD) on each end of the four-helix bundle (red) (2VRZ) ( ). Crystal structure of PE25 (light blue) and PPE41 (dark blue) of in complex with the chaperone EspG (yellow). EspG interacts with the PPE protein through hydrophobic interactions but not directly with the PE protein. The WxG motif on the PPE and the YxxxE motif on the PE protein together form a putative T7S signal (red residues) (4KXR) ( ). Crystal structure of monomeric EspB visualizing an extended secretion signal that includes the YxxxD/E and WxG motif (red residues) (3J83) ( ).

Citation: Ates L, Houben E, Bitter W. 2016. Type VII Secretion: A Highly Versatile Secretion System, p 357-384. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed),

Virulence Mechanisms of Bacterial Pathogens, Fifth Edition

. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.VMBF-0011-2015
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Image of Figure 4
Figure 4

Crystal structures of EccC of . C-terminal domains of EccC containing all three NBDs or containing only NBD2 and NBD3 and with a bound secretion signal of EsxB are shown as described by Rosenberg et al. ( ). The secretion signal (in green) is bound to a hydrophobic pocket of NBD3. While NBD2 and NBD3 have a bound ATP molecule (red), NBD1 has a sulfate ion at the ATP binding site instead (in orange). NBD1 activity is inhibited by a linker domain of NBD2. This inhibition can be alleviated by changing arginine 543 (the orange residue) to an alanine.

Citation: Ates L, Houben E, Bitter W. 2016. Type VII Secretion: A Highly Versatile Secretion System, p 357-384. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed),

Virulence Mechanisms of Bacterial Pathogens, Fifth Edition

. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.VMBF-0011-2015
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