The E3 Ligase Parkin Maintains Mitochondrial Integrity by Increasing Linear Ubiquitination of NEMO

Anne Kathrin Müller-Rischart, Anna Pilsl, Patrick Beaudette, Maria Patra, Kamyar Hadian, Maria Funke, Regina Peis, Alexandra Deinlein, Carolin Schweimer, Peer Hendrik Kuhn, Stefan F. Lichtenthaler, Elisa Motori, Silvana Hrelia, Wolfgang Wurst, Dietrich Trümbach, Thomas Langer, Daniel Krappmann, Gunnar Dittmar, Jörg Tatzelt, Konstanze F. Winklhofer*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

167 Citations (Scopus)

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-κB 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-κB essential modulator (NEMO), which is essential for canonical NF-κB signaling. As a result, the mitochondrial guanosine triphosphatase OPA1 is transcriptionally upregulated via NF-κB-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-κB, and upregulation of OPA1 are significantly reduced in response to TNF-α stimulation, supporting the physiological relevance of parkin in regulating this antiapoptotic pathway.

Original languageEnglish
Pages (from-to)908-921
Number of pages14
JournalMolecular Cell
Volume49
Issue number5
DOIs
Publication statusPublished - 7 Mar 2013
Externally publishedYes

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