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Dissertation zugänglich unter
The impact of Yersinia enterocolitica (Schleifstein and Coleman, 1939) virulence factors on Rho GTPases in host cells
Dokument 1.pdf (3.214 KB)
Freie Schlagwörter (Englisch):
RhoG , YopE , RhoGAP, Elmo , Invasin
42.30 , 42.15
Aepfelbacher, Martin (Prof. Dr.)
Tag der mündlichen Prüfung:
Kurzfassung auf Englisch:
Pathogenic bacteria of the genus Yersinia (Y. pestis, Y. pseudotuberculosis and Y. enterocolitica) have evolved numerous ways to manipulate the activity of Rho GTPases and establish a successful infection. Rho GTPases are activated by Yersinia adhesins to trigger invasion and inactivated by Yersinia effector Yops (i.e. YopE, YopT, YpkA/YopO) to suppress immune cell functions. Using biochemical assays and fluorescence imaging, RhoG, a Rac-related protein that can act as an upstream regulator of other Rho GTPases, was found to be initially activated and then deactivated during Yersinia infection of cells. The ß1-integrin-clustering protein, invasin, on the bacterial surface, was identified as being crucial for RhoG activation, thereby promoting cell invasion.
On the other hand, the type III secretion system effector YopE downregulated active RhoG by acting as a Rho GTPase activating protein. While non-virulent yersiniae were internalized by cultured cells within only a few minutes, internalization of a virulent Yersinia strain could last up to 23 minutes. Under these conditions spatiotemporally organized activation and deactivation of RhoG could be visualized at the contact site of virulent Y. enterocolitica and host cells.
YopE localization to the Golgi apparatus and endoplasmatic reticulum, mediated by its membrane localization domain, determined its substrate specificity for RhoG and other selected Rho GTPases. RhoG was found to be responsible for invasin-stimulated Rac1 activation and inactivation of RhoG was entirely responsible for downregulation of endogenously active Rac1 by YopE. In addition, direct Rac1 activation by the guanine nucleotide exchange factor Tiam1 could be inhibited but not abrogated by YopE. These experiments show that RhoG is a central target of both, stimulatory and inhibitory Yersinia virulence factors. By controlling RhoG, Yersinia abolishes some specific Rac1 activation pathways but leaves intact, at least partially, alternative Rac1 activation pathways. Thus, by targeting of RhoG, Yersinia can fine tune Rac1 activity in host cells, which adds another level of complexity by which Yersinia modulates Rho GTPase signaling networks.
These results provide novel information on molecular mechanisms of Yersinia infection and gives new insights into the pathogenicity of Yersinia.