title: Destabilization of YopE by the ubiquitin-proteasome pathway fine-tunes Yop delivery into host cells and facilitates systemic spread of Yersinia enterocolitica in host lymphoid tissue.
abstract: Pathogenic Yersinia species inject a panel of Yop virulence proteins by type III protein secretion into host cells to modulate cellular defense responses. This enables the survival and dissemination of the bacteria in the host lymphoid tissue. We have previously shown that YopE of the Y. enterocolitica serogroup O8 is degraded in the host cell through the ubiquitin-proteasome pathway. YopE normally manipulates rearrangements of the actin cytoskeleton and triggers phagocytosis resistance. To shed light into the physiological role of YopE inactivation, we mutagenized the lysine polyubiquitin acceptor sites of YopE in the Y. enterocolitica serogroup O8 virulence plasmid. The resulting mutant strain escaped polyubiquitination and degradation of YopE and displayed increased intracellular YopE levels, which was accompanied by a pronounced cytotoxic effect on infected cells. Despite its intensified activity on cultured cells, the Yersinia mutant with stabilized YopE showed reduced dissemination into liver and spleen following enteral infection of mice. Furthermore, the accumulation of degradation-resistant YopE was accompanied by the diminished delivery of YopP and YopH into cultured, Yersinia-infected cells. A role of YopE in the regulation of Yop translocation has already been described. Our results imply that the inactivation of YopE by the proteasome could be a tool to ensure intermediate intracellular YopE levels, which may effectuate optimized Yop injection into host cells. In this regard, Y. enterocolitica O8 appears to exploit the host ubiquitin proteasome system to destabilize YopE and to fine-tune the activities of the Yop virulence arsenal on the infected host organism.
authors.affiliation: Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Gaus
authors.forename: Moritz
authors.initials: M
authors.lastname: Hentschke
authors.forename: Nicole
authors.initials: N
authors.lastname: Czymmeck
authors.forename: Lena
authors.initials: L
authors.lastname: Novikova
authors.forename: Konrad
authors.initials: K
authors.lastname: Trülzsch
authors.forename: Peter
authors.initials: P
authors.lastname: Valentin-Weigand
authors.forename: Martin
authors.initials: M
authors.lastname: Aepfelbacher
authors.forename: Klaus
authors.initials: K
authors.lastname: Ruckdeschel
mesh_terms: D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002460:Cell Line; D005260:Female; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008221:Lymphoid Tissue / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism; D014774:Virulence / Q000502:physiology; D015009:Yersinia Infections / Q000235:genetics / Q000378:metabolism*; D015008:Yersinia enterocolitica / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*
chemical_list: D001425:Bacterial Outer Membrane Proteins; D025801:Ubiquitin; C063239:yopE protein, Yersinia; D046988:Proteasome Endopeptidase Complex