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Mol Cell. 2013 Mar 7;49(5):908-21. doi: 10.1016/j.molcel.2013.01.036. Epub 2013 Feb 28.

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

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1
Neurobiochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, 80336 Munich, Germany.

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.

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PMID:
23453807
DOI:
10.1016/j.molcel.2013.01.036
[Indexed for MEDLINE]
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