Parkin mediates neuroprotection through activation of IkappaB kinase/nuclear factor-kappaB signaling.
Mutations in the parkin gene are a major cause of autosomal recessive Parkinson's disease. Here we show that the E3 ubiquitin ligase parkin activates signaling through the IkappaB kinase (IKK)/nuclear factor kappaB (NF-kappaB) pathway. Our analysis revealed that activation of this signaling cascade is causally linked to the neuroprotective potential of parkin. Inhibition of NF-kappaB activation by an IkappaB super-repressor or a kinase-inactive IKKbeta interferes with the neuroprotective activity of parkin. Furthermore, pathogenic parkin mutants with an impaired neuroprotective capacity show a reduced ability to stimulate NF-kappaB-dependent transcription. Finally, we present evidence that parkin interacts with and promotes degradation-independent ubiquitylation of IKKgamma/NEMO (NF-kappaB essential modifier) and TRAF2 [TNF (tumor necrosis factor) receptor-associated factor 2], two critical components of the NF-kappaB pathway. Thus, our results support a direct link between the neuroprotective activity of parkin and ubiquitin signaling in the IKK/NF-kappaB pathway.
Henn
Iris H
IH
Department of Biochemistry, Adolf-Butenandt-Institute, D-80336 Munich, Germany.
Bouman
Lena
L
Schlehe
Julia S
JS
Schlierf
Anita
A
Schramm
Julia E
JE
Wegener
Elmar
E
Nakaso
Kazuhiro
K
Culmsee
Carsten
C
Berninger
Benedikt
B
Krappmann
Daniel
D
Tatzelt
Jörg
J
Winklhofer
Konstanze F
KF
D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*
D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D051550:I-kappa B Kinase