Abstract
The type III secretion system (T3SS) is a complex molecular device used by several pathogenic bacteria to translocate effector proteins directly into eukaryotic host cells. One remarkable feature of the T3SS is its ability to secrete different categories of proteins in a hierarchical manner, to ensure proper assembly and timely delivery of effectors into target cells. In enteropathogenic Escherichia coli, the substrate specificity switch from translocator to effector secretion is regulated by a gatekeeper complex composed of SepL, SepD, and CesL proteins. Here, we report a characterization of the CesL protein using biochemical and genetic approaches. We investigated discrepancies in the phenotype among different cesL deletion mutants and showed that CesL is indeed essential for translocator secretion and to prevent premature effector secretion. We also demonstrated that CesL engages in pairwise interactions with both SepL and SepD. Furthermore, while association of SepL to the membrane does not depended on CesL, the absence of any of the proteins forming the heterotrimeric complex compromised the intracellular stability of each component. In addition, we found that CesL interacts with the cytoplasmic domains of the export gate components EscU and EscV. We propose a mechanism for substrate secretion regulation governed by the SepL/SepD/CesL complex.
Highlights
Enteropathogenic Escherichia coli (EPEC) is a causal agent of human intestinal disease generating acute watery diarrhea in children [1]
The secretion phenotype of a Citrobacter rodentium (CR) cesL mutant was reported to be a general defect in both translocator and effector protein secretion [54], and the same was observed for a cesL (l0036) mutant in enterohemorrhagic E. coli (EHEC) [60]
We revisited the EPEC cesL mutant phenotype, demonstrating that CesL is crucial for translocator protein secretion and negatively regulates effector protein secretion (Figure 1A)
Summary
Enteropathogenic Escherichia coli (EPEC) is a causal agent of human intestinal disease generating acute watery diarrhea in children [1]. A central element to EPEC pathogenicity is a type III secretion system (T3SS) or injectisome, which translocates effector proteins into the enterocyte cytosol [5,6]. The T3SS in AE pathogens is encoded on a chromosomal pathogenicity island known as locus of enterocyte effacement (LEE), which comprises 41 genes arranged into seven operons and four individual transcriptional entities [7,8,9]. Seven of the translocated effectors are encoded within the LEE, while the genes for around 16 others (named Nle, for non-LEE encoded effectors) are distributed elsewhere in the chromosome [10,11].
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