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Animals
Apoptosis
Fibroblasts/metabolism
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins/genetics/*metabolism
Mice
Mice, Knockout
Mitochondria/*metabolism
NF-kappa B/genetics/metabolism
Neurons/metabolism
Parkinson Disease/genetics/metabolism
Signal Transduction
Transfection
Ubiquitin-Protein Ligases/*genetics/metabolism
Ubiquitination/*genetics
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.
