TY  - JOUR
AU  - Müller-Rischart, A. Kathrin
AU  - Pilsl, Anna
AU  - Beaudette, Patrick
AU  - Patra, Maria
AU  - Hadian, Kamyar
AU  - Funke, Maria
AU  - Peis, Regina
AU  - Deinlein, Alexandra
AU  - Schweimer, Carolin
AU  - Kuhn, Peer-Hendrik
AU  - Lichtenthaler, Stefan F
AU  - Motori, Elisa
AU  - Hrelia, Silvana
AU  - Wurst, Wolfgang
AU  - Trümbach, Dietrich
AU  - Langer, Thomas
AU  - Krappmann, Daniel
AU  - Dittmar, Gunnar
AU  - Tatzelt, Jörg
AU  - Winklhofer, Konstanze F
TI  - The E3 ligase parkin maintains mitochondrial integrity by increasing linear ubiquitination of NEMO.
JO  - Molecular cell
VL  - 49
IS  - 5
SN  - 1097-2765
CY  - New York, NY
PB  - Elsevier
M1  - DZNE-2020-03161
SP  - 908-921
PY  - 2013
AB  - 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.
KW  - Animals
KW  - Apoptosis
KW  - Fibroblasts: metabolism
KW  - HEK293 Cells
KW  - Humans
KW  - Intracellular Signaling Peptides and Proteins: genetics
KW  - Intracellular Signaling Peptides and Proteins: metabolism
KW  - Mice
KW  - Mice, Knockout
KW  - Mitochondria: metabolism
KW  - NF-kappa B: genetics
KW  - NF-kappa B: metabolism
KW  - Neurons: metabolism
KW  - Parkinson Disease: genetics
KW  - Parkinson Disease: metabolism
KW  - Signal Transduction
KW  - Transfection
KW  - Ubiquitin-Protein Ligases: genetics
KW  - Ubiquitin-Protein Ligases: metabolism
KW  - Ubiquitination: genetics
KW  - Intracellular Signaling Peptides and Proteins (NLM Chemicals)
KW  - NEMO protein, mouse (NLM Chemicals)
KW  - NF-kappa B (NLM Chemicals)
KW  - Ubiquitin-Protein Ligases (NLM Chemicals)
KW  - parkin protein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:23453807
DO  - DOI:10.1016/j.molcel.2013.01.036
UR  - https://pub.dzne.de/record/136839
ER  -