Eingang zum Volltext in OPUS
Hinweis zum Urheberrecht
Dissertation zugänglich unter
The role of cytotoxic necrotizing factor 1-induced activation of RhoG during uropathogenic Escherichia coli infections
Die Rolle der durch den zytotoxisch nekrotisierenden Faktor 1-induzierten Aktivierung von RhoG während uropathogener E. coli Infektionen
Dokument 1.pdf (6.197 KB)
42.15 , 42.30
Aepfelbacher, Martin (Prof. Dr.)
Tag der mündlichen Prüfung:
Kurzfassung auf Englisch:
Virulence factors enable the pathogen to overcome host barriers, facilitating many steps during the infection process, ranging from adherence, uptake into host cells, and evasion from the immune system to finally establishing a niche for replication. Uropathogenic Escherichia coli (UPEC) encode a variety of virulence factors allowing the bacteria to persist in the urinary tract in the face of host defenses. In addition to antibiotic resistance mechanisms, many UPEC virulence factors make infections refractory to medical treatment. Therefore, it is of great interest to understand underlying pathogenic mechanisms of UPEC infections. The virulence factor cytotoxic necrotizing factor 1 (CNF1) is a toxin expressed by many extraintestinal pathogenic E. coli (ExPEC) strains. It belongs to a group of toxins that manipulate several host functions by covalent modification of Rho GTPases. Rho GTPases are molecular switches that regulate many important cellular processes, most prominent of which are the rearrangements of the actin cytoskeleton. Through its ability to modulate Rho GTPases, CNF1 facilitates bacterial internalization and is implicated in regulation of host immune responses. CNF1 has previously been shown to activate the Rho GTPases Rac1, RhoA and Cdc42 by deamidation of the conserved glutamine 61/63. The abundance of activated Rho GTPases is subsequently attenuated by ubiquitin-mediated proteasomal degradation. This study demonstrates that the less studied Rho GTPase RhoG is strongly, but transiently activated upon intoxication with CNF1 but not upon intoxication with the closely related CNFy toxin from Yersinia pseudotuberculosis. Using mass spectrometry, it was shown that CNF1 deamidates glutamine at position 61 of RhoG. Investigation of the functional role of CNF1-activated RhoG during UPEC infection revealed that RhoG is not responsible for the induction of CNF1-induced proinflammatory signaling pathways. Instead, RhoG was found to be strongly recruited to sites of UPEC infection where it had an inhibitory effect on invasion. Invasion of UPEC is primarily Rac1-dependent, and therefore, possible crosstalk between RhoG and Rac1 was explored. However, CNF1-activated RhoG did not reduce Rac1 activation or change the subcellular localization of Rac1 or the rate of Rac1 degradation.
In conclusion, these data demonstrate that RhoG is a novel target of CNF1 and implicate CNF1-induced activation of RhoG in bacterial invasion. This study enhances our understanding of host-pathogen interactions during UPEC infection as well as sheds light on the dynamic crosstalk between Rho GTPases.