Yersinia YopP-induced apoptotic cell death in murine dendritic cells is partially independent from action of caspases and exhibits necrosis-like features.
Yersinia outer protein P (YopP) is a virulence factor of Yersinia enterocolitica that is injected into the cytosol of host cells where it targets MAP kinase kinases (MKKs) and inhibitor of kappaB kinase (IKK)-beta resulting in inhibition of cytokine production as well as induction of apoptosis in murine macrophages and dendritic cells (DC). Here we show that DC death was only partially prevented by the broad spectrum caspase inhibitor zVAD-fmk, indicating simultaneous caspase-dependent and caspase-independent mechanisms of cell death induction by YopP. Microscopic analyses and measurement of cell size demonstrated necrosis-like morphology of caspase-independent cell death. Application of zVAD-fmk prevented cleavage of procaspases and Bid, decrease of the inner transmembrane mitochondrial potential DeltaPsi(m) and mitochondrial release of cytochrome c. From these data we conclude that YopP-induced activation of the mitochondrial death pathway is mediated upstream via caspases. In conclusion, our results suggest that YopP simultaneously induces caspase-dependent apoptotic and caspase-independent necrosis-like death in DC. However, it has to be resolved if necrosis-like DC death occurs independently from apoptotic events or as an apoptotic epiphenomenon.
Gröbner
Sabine
S
Institute of Medical Microbiology and Hygiene, Eberhard-Karls-University of Tübingen, Elfriede-Aulhorn-Str. 6, D-72076, Tübingen, Germany. sabine.groebner@med.uni-tuebingen.de
Autenrieth
Stella E
SE
Soldanova
Irena
I
Gunst
Dani S J
DS
Schaller
Martin
M
Bohn
Erwin
E
Müller
Steffen
S
Leverkus
Martin
M
Wesselborg
Sebastian
S
Autenrieth
Ingo B
IB
Borgmann
Stefan
S
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001426:Bacterial Proteins / Q000378:metabolism*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D048429:Cell Size; D045304:Cytochromes c / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000382:microbiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D024243:HMGB1 Protein / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009336:Necrosis; D015009:Yersinia Infections / Q000276:immunology / Q000378:metabolism; D015008:Yersinia enterocolitica / Q000472:pathogenicity*
D000590:Amino Acid Chloromethyl Ketones; D001426:Bacterial Proteins; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D024243:HMGB1 Protein; C109227:YopP protein, Yersinia; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D045304:Cytochromes c; D020169:Caspases