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-kB 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-kB essential modulator (NEMO), which is essential for canonical NF-kB signaling. As a result, the mitochondrial guanosine triphosphatase OPA1 is transcriptionally upregulated via NF-kB-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-kB, and upregulation of OPA1 are significantly reduced in response to TNF-alpha stimulation, supporting the physiological relevance of parkin in regulating this antiapoptotic pathway.
Müller-Rischart A.K., Pilsl A., Beaudette P., Patra M., Hadian K., Funke M., et al. (2013). The E3 Ligase Parkin Maintains Mitochondrial Integrity by Increasing Linear Ubiquitination of NEMO. MOLECULAR CELL, 49(5), 908-921 [10.1016/j.molcel.2013.01.036].
The E3 Ligase Parkin Maintains Mitochondrial Integrity by Increasing Linear Ubiquitination of NEMO
HRELIA, SILVANA;
2013
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-kB 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-kB essential modulator (NEMO), which is essential for canonical NF-kB signaling. As a result, the mitochondrial guanosine triphosphatase OPA1 is transcriptionally upregulated via NF-kB-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-kB, and upregulation of OPA1 are significantly reduced in response to TNF-alpha stimulation, supporting the physiological relevance of parkin in regulating this antiapoptotic pathway.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
