title: Catalytically active Yersinia outer protein P induces cleavage of RIP and caspase-8 at the level of the DISC independently of death receptors in dendritic cells.
abstract: Yersinia outer protein P (YopP) is injected by Y. enterocolitica into host cells thereby inducing apoptotic and necrosis-like cell death in dendritic cells (DC). Here we show the pathways involved in DC death caused by the catalytic activity of YopP. Infection with Yersinia enterocolitica, translocating catalytically active YopP into DC, triggered procaspase-8 cleavage and c-FLIPL degradation. YopP-dependent caspase-8 activation was, however, not mediated by tumor necrosis factor (TNF) receptor family members since the expression of both CD95/Fas/APO-1 and TRAIL-R2 on DC was low, and DC were resistant to apoptosis induced by agonistic anti-CD95 antibodies or TNF-related apoptosis-inducing ligand (TRAIL). Moreover, DC from TNF-Rp55-/- mice were not protected against YopP-induced cell death demonstrating that TNF-R1 is also not involved in this process. Activation of caspase-8 was further investigated by coimmunoprecitation of FADD from Yersinia-infected DC. We found that both cleaved caspase-8 and receptor interacting protein 1 (RIP1) were associated with the Fas-associated death domain (FADD) indicating the formation of an atypical death-inducing signaling complex (DISC). Furthermore, degradation of RIP mediated by the Hsp90 inhibitor geldanamycin significantly impaired YopP-induced cell death. Altogether our findings indicate that Yersinia-induced DC death is independent of death domain containing receptors, but mediated by RIP and caspase-8 at the level of DISC.
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Elfriede-Aulhorn-Str., 6, 72076, Tuebingen, Germany. sabine.groebner@med.uni-tuebingen.de
authors.forename: Sabine
authors.initials: S
authors.lastname: Gröbner
authors.forename: Irena
authors.initials: I
authors.lastname: Adkins
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schulz
authors.forename: Kathleen
authors.initials: K
authors.lastname: Richter
authors.forename: Stefan
authors.initials: S
authors.lastname: Borgmann
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wesselborg
authors.forename: Klaus
authors.initials: K
authors.lastname: Ruckdeschel
authors.forename: Olivier
authors.initials: O
authors.lastname: Micheau
authors.forename: Ingo B
authors.initials: IB
authors.lastname: Autenrieth
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D016227:Benzoquinones / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D053218:Receptors, Death Domain / Q000235:genetics / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015008:Yersinia enterocolitica / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D016227:Benzoquinones; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053418:Death Domain Receptor Signaling Adaptor Proteins; D004791:Enzyme Inhibitors; D053200:Fas-Associated Death Domain Protein; D047029:Lactams, Macrocyclic; D053218:Receptors, Death Domain; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D047888:Receptors, Tumor Necrosis Factor, Type I; C109227:YopP protein, Yersinia; D019014:fas Receptor; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053181:Caspase 8; C001277:geldanamycin