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

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Item Type:	Article
Title:	The E3 ligase parkin maintains mitochondrial integrity by increasing linear ubiquitination of NEMO
Creators Name:	Mueller-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, Truembach, D., Langer, T., Krappmann, D., Dittmar, G., 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
ISSN:	1097-2765
Publisher:	Cell Press
Volume:	49
Number:	5
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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