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Müller-Rischart, A.K.* ; Pilsl, A.* ; Beaudette, P.* ; Patra, M.* ; Hadian, K. ; Funke, M.* ; Peis, R. ; Deinlein, A.* ; Schweimer, C.* ; Kuhn, P.-H.* ; Lichtenthaler, S.F.* ; Motori, E.* ; Hrelia, S.* ; Wurst, W. ; Trümbach, D. ; Langer, T.* ; Krappmann, D. ; Dittmar, G.* ; Tatzelt, J.* ; Winklhofer, K.F.*

The E3 ligase Parkin maintains mitochondrial integrity by increasing linear ubiquitination of NEMO.

Mol. Cell 49, 908-921 (2013)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Parkin, a RING-between-RING-type E3 ubiquitin ligase associated with Parkinson's disease, has a wide neuroprotective activity, preventing cell death in various stress paradigms. We identified a stress-protective pathway regulated by parkin that links NF-kappa B signaling and mitochondrial integrity via linear ubiquitination. Under cellular stress, parkin is recruited to the linear ubiquitin assembly complex and increases linear ubiquitination of NF-kappa B essential modulator (NEMO), which is essential for canonical NF-kappa B signaling. As a result, the mitochondrial guanosine triphosphatase OPA1 is transcriptionally upregulated via NF-kappa B-responsive promoter elements for maintenance of mitochondrial integrity and protection from stress-induced cell death. Parkin-induced stress protection is lost in the absence of either NEMO or OPA1, but not in cells defective for the mitophagy pathway. Notably, in parkin-deficient cells linear ubiquitination of NEMO, activation of NF-kappa B, and upregulation of OPA1 are significantly reduced in response to TNF-alpha stimulation, supporting the physiological relevance of parkin in regulating this antiapoptotic pathway.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Kappa-b Activation ; Chain Assembly Complex ; Cytochrome-c Release ; Incontinentia Pigmenti ; Polyubiquitin Chains ; Disease ; Inflammation ; Sharpin ; Contributes ; Recruitment
ISSN (print) / ISBN 1097-2765
e-ISSN 1097-4164
Journal Molecular Cell
Quellenangaben Volume: 49, Issue: 5, Pages: 908-921 Article Number: , Supplement: ,
Publisher Elsevier
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Toxicology and Pharmacology (TOXI)
Institute of Developmental Genetics (IDG)
Research Unit Signaling and Translation (SAT)