Abstract
Many bacteria export effector proteins fulfilling their function in membranes of a eukaryotic host. These effector membrane proteins appear to contain signals for two incompatible bacterial secretion pathways in the same protein: a specific export signal, as well as transmembrane segments that one would expect to mediate targeting to the bacterial inner membrane. Here, we show that the transmembrane segments of effector proteins of type III and type IV secretion systems indeed integrate in the membrane as required in the eukaryotic host, but that their hydrophobicity in most instances is just below the threshold required for mediating targeting to the bacterial inner membrane. Furthermore, we show that binding of type III secretion chaperones to both the effector’s chaperone-binding domain and adjacent hydrophobic transmembrane segments also prevents erroneous targeting. These results highlight the evolution of a fine discrimination between targeting pathways that is critical for the virulence of many bacterial pathogens.
Highlights
Many bacteria export effector proteins fulfilling their function in membranes of a eukaryotic host
Remarkable is the dominance of inclusion membrane proteins (Incs) proteins of Chlamydia among the T3SS Transmembrane domains (TMDs)-substrates, of which we have only included the proteins of one sequenced isolate but of which a set of much greater diversity is known[16]
This analysis illustrates that T3SS commonly secrete TMD-substrates with effector functions other than translocators and suggests that T3SS favor the secretion of transmembrane proteins with TMDs of lower complexity
Summary
Many bacteria export effector proteins fulfilling their function in membranes of a eukaryotic host. We show that the transmembrane segments of effector proteins of type III and type IV secretion systems integrate in the membrane as required in the eukaryotic host, but that their hydrophobicity in most instances is just below the threshold required for mediating targeting to the bacterial inner membrane. In bacteria utilizing T3SS, posttranslational T3SS-dependent secretion of substrates needs to be ensured even if these proteins expose a potential signal for cotranslational membrane targeting and integration. A second factor for targeting discrimination, at least for some T3SS substrates, is the binding of their CBD and TMS by their cognate chaperones This chaperone binding even prevents inner membrane targeting and insertion of TMS that are sufficiently hydrophobic for SRP-dependent targeting. Our results indicate that a TMS-specific co-translational targeting mechanism by T3SS chaperones prevents co-translational mistargeting such as by the SRP for subsequent post-translational secretion of membrane proteins through the T3SS injectisome
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