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

Item Type:Article
Title:The E3 ligase parkin maintains mitochondrial integrity by increasing linear ubiquitination of NEMO
Creators Name:Mueller-Rischart, A.K. and Pilsl, A. and Beaudette, P. and Patra, M. and Hadian, K. and Funke, M. and Peis, R. and Deinlein, A. and Schweimer, C. and Kuhn, P.H. and Lichtenthaler, S.F. and Motori, E. and Hrelia, S. and Wurst, W and Truembach, D. and Langer, T. and Krappmann, D. and Dittmar, G. and Tatzelt, J. and Winklhofer, K.F.
Abstract: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-kappaB 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-kappaB essential modulator (NEMO), which is essential for canonical NF-kappaB signaling. As a result, the mitochondrial guanosine triphosphatase OPA1 is transcriptionally upregulated via NF-kappaB-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-kappaB, and upregulation of OPA1 are significantly reduced in response to TNF-alpha stimulation, supporting the physiological relevance of parkin in regulating this antiapoptotic pathway.
Keywords:Apoptosis, Fibroblasts, HEK293 Cells, Intracellular Signaling Peptides and Proteins, Knockout Mice, Mitochondria, NF-kappa B, Neurons, Parkinson Disease, Signal Transduction, Transfection, Ubiquitin-Protein Ligases, Ubiquitination, Animals, Mice
Source:Molecular Cell
Publisher:Cell Press
Page Range:908-921
Date:7 March 2013
Official Publication:https://doi.org/10.1016/j.molcel.2013.01.036
PubMed:View item in PubMed

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