Abstract
Pathogens use diverse molecular machines to penetrate host cells and manipulate intracellular vesicular trafficking. Viruses employ glycoproteins, functionally and structurally similar to the SNARE proteins, to induce eukaryotic membrane fusion. Intracellular pathogens, on the other hand, need to block fusion of their infectious phagosomes with various endocytic compartments to escape from the degradative pathway. The molecular details concerning the mechanisms underlying this process are lacking. Using both an in vitro liposome fusion assay and a cellular assay, we showed that SNARE-like bacterial proteins block membrane fusion in eukaryotic cells by directly inhibiting SNARE-mediated membrane fusion. More specifically, we showed that IncA and IcmG/DotF, two SNARE-like proteins respectively expressed by Chlamydia and Legionella, inhibit the endocytic SNARE machinery. Furthermore, we identified that the SNARE-like motif present in these bacterial proteins encodes the inhibitory function. This finding suggests that SNARE-like motifs are capable of specifically manipulating membrane fusion in a wide variety of biological environments. Ultimately, this motif may have been selected during evolution because it is an efficient structural motif for modifying eukaryotic membrane fusion and thus contribute to pathogen survival.
Highlights
In eukaryotic cells, intracellular membrane fusion events are mediated by members of the SNARE protein family
Intracellular bacteria primarily protect their vacuoles against endocytic fusion [12,25], which is mediated by the association of the v-SNARE VAMP8 with the endocytic t-SNARE composed of Syntaxin 7, Syntaxin 8 and Vti1b [26,27]
Using CtrIncA, CcaIncA and IcmG/DotF as our models, we demonstrated that SNARE-like bacterial proteins differentially block SNAREsmediated membrane fusion
Summary
Intracellular membrane fusion events are mediated by members of the SNARE protein family. T-SNAREs present on target organelles assemble into a four-helix bundle with the v-SNAREs present on vesicles. This event brings the membranes in which they are embedded into close apposition and drives bilayer fusion [4,5,6,7]. The SNARE residues indispensable for membrane fusion form the ‘‘SNARE motif’’ [6], a 60 amino-acid sequence composed of coiled-coil heptad repeats [Table 1 and [8]]. Similar structural motifs are used for the same purpose by viruses, highlighting the general role of coiled coil sequences in manipulating membrane fusion [9,10]. We investigated whether this particular motif is utilized by bacteria to influence eukaryotic membrane fusion
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