Abstract
Bartonella spp. are facultative intracellular pathogens that infect a wide range of mammalian hosts including humans. In order to subvert cellular functions and the innate immune response of their hosts, these pathogens utilize a VirB/VirD4 type-IV-secretion (T4S) system to translocate Bartonella effector proteins (Beps) into host cells. Crucial for this process is the Bep intracellular delivery (BID) domain that together with a C-terminal stretch of positively charged residues constitutes a bipartite T4S signal. This function in T4S is evolutionarily conserved with BID domains present in bacterial toxins and relaxases. Strikingly, some BID domains of Beps have evolved secondary functions to modulate host cell and innate immune pathways in favor of Bartonella infection. For instance, BID domains mediate F-actin-dependent bacterial internalization, inhibition of apoptosis, or modulate cell migration. Recently, crystal structures of three BID domains from different Beps have been solved, revealing a conserved fold formed by a four-helix bundle topped with a hook. While the conserved BID domain fold might preserve its genuine role in T4S, the highly variable surfaces characteristic for BID domains may facilitate secondary functions. In this review, we summarize our current knowledge on evolutionary and structural traits as well as functional aspects of the BID domain with regard to T4S and pathogenesis.
Highlights
Type-IV-secretion (T4S) systems are multiprotein complexes embedded in the cell envelope of Gram-negative and Gram-positive bacteria and some archaea (Berge et al, 2017)
The Bep intracellular delivery (BID) domain constitutes together with a positively charged C-terminal tail a T4S-signal that is crucial for the interbacterial transfer of relaxases and protein toxins by various α-proteobacteria and for the interkingdom transfer of effectors by pathogenic Bartonella spp
On the basis of the recently solved BID domain structures, their conserved fold may play a crucial role in T4S, whereas the plasticity of the surfaces seems to have facilitated novel interaction areas with host target proteins (Stanger et al, 2017)
Summary
Type-IV-secretion (T4S) systems are multiprotein complexes embedded in the cell envelope of Gram-negative and Gram-positive bacteria and some archaea (Berge et al, 2017) They represent versatile nanomachines that fulfill diverse functions including (1) contact-dependent transfer of DNA (conjugation), (2) contact-dependent transfer of bacterial effector proteins into eukaryotic host cells, (3) contact-dependent toxin delivery into bacterial cells, (4) secretion of DNA into the extracellular milieu, and (5) uptake of DNA from the environment (Waksman, 2019). Some T4S signals form a larger structural scaffold, as for instance, the globular TSA domain of conjugative relaxase TraI encoded by plasmid R1 (Redzej et al, 2013) Another example constitutes the approximately 100-aa-long BID (Bep intracellular delivery) domain that together with a short positively charged C-terminal tail forms a bipartite T4S signal proposed to interact with the T4CP (Schulein et al, 2005; Stanger et al, 2017). We will discuss structural and functional aspects of the BID domain with regard to T4S and the subversion of host cell function
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