title: The E3 ligase parkin maintains mitochondrial integrity by increasing linear ubiquitination of NEMO.
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.
authors: Neurobiochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, 80336 Munich, Germany.
authors: Anne Kathrin
authors: AK
authors: Müller-Rischart
authors: Anna
authors: A
authors: Pilsl
authors: Patrick
authors: P
authors: Beaudette
authors: Maria
authors: M
authors: Patra
authors: Kamyar
authors: K
authors: Hadian
authors: Maria
authors: M
authors: Funke
authors: Regina
authors: R
authors: Peis
authors: Alexandra
authors: A
authors: Deinlein
authors: Carolin
authors: C
authors: Schweimer
authors: Peer-Hendrik
authors: PH
authors: Kuhn
authors: Stefan F
authors: SF
authors: Lichtenthaler
authors: Elisa
authors: E
authors: Motori
authors: Silvana
authors: S
authors: Hrelia
authors: Wolfgang
authors: W
authors: Wurst
authors: Dietrich
authors: D
authors: Trümbach
authors: Thomas
authors: T
authors: Langer
authors: Daniel
authors: D
authors: Krappmann
authors: Gunnar
authors: G
authors: Dittmar
authors: Jörg
authors: J
authors: Tatzelt
authors: Konstanze F
authors: KF
authors: Winklhofer
mesh_terms: D000818:Animals; D017209:Apoptosis; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein