Andre Kraus


B10 Molecular function and signal transduction of the serine protease HtrA, a novel secreted effector protein of bacterial pathogens

Principal investigator
Steffen Backert


Molecular functions of the serine protease HtrA in enteric bacterial pathogens

In mammals, the intact epithelial cell layer at mucosal surfaces serves as a functional barrier against all kinds of intruding pathogens. One of them is the food-borne bacterium Campylobacter jejuni, which is considered as a classic zoonotic pathogen. It has been shown, that C. jejuni colonizes wild and domestic birds and mammals such as cows and pigs. Recently it has been shown that a closely related enteric pathogen named Helicobacter pylori secretes a novel bacterial virulence determinant into the culture supernatant during the infection progress, the serine protease HtrA, which was later shown to be also present in C. jejuni.
The protease HtrA consists of a signal peptide, a trypsine-like protease domain and one or two protein interaction domains (PDZ). HtrA is also able to form oligomers that can function as chaperons. Many bacterial HtrA were postulated to be periplasmatic proteins. Surprisingly, we could recently show that HtrA of H. pylori was able to be secreted and thereafter can cleave host cell surface molecules such as the adherens junctional and tumor suppressor protein E-cadherin. This leads to the loss of cell-cell junctions. Since this mechanism could represent an omnipresent mechanism of cell invasion, this project is concentrating on the functional characterization of the HtrA secretion mechanism in enteric bacteria.

Figure: Proposed model of transmigration process of C. jejuni across polarised epithelial cells.
a) C. jejuni colonises the mucus layer apical to the intestinal epithelium; b) Bacteria start to secrete HtrA protease into the extracellular space, resulting in a cleavage of E-cadherin and probably other junctional proteins; c) Opening of cell-to-cell junctions, allowing C. jejuni passing through the cell monolyer (paracellular route); d) C. jejuni binding basolateral to fibronectin/ integrin host cell receptor complex and activate different signaling cascades involved in invasion; e) Engulfment of uptake into the host target cells. Closure of the junctions behind the bacteria. Entrance of bacteria into cytoplasm where they trigger tissue damage followed by serious diseases. (Modified after Böhm et al. 2012).