TY - JOUR
T1 - The E3 Ligase Parkin Maintains Mitochondrial Integrity by Increasing Linear Ubiquitination of NEMO
AU - Müller-Rischart, Anne 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.
N1 - Funding Information:
We thank Drs. Alexis Brice and Olga Corti for providing parkin KO mice, Marc Schmidt-Supprian for NEMO KO MEFs, Jean-Claude Martinou for OPA1 KO MEFs, Noboru Mizushima for ATG5 KO MEFs, Tetsuro Ishii for p62 KO MEFs, and Heidi McBride for the OPA1 plasmid. We also thank Daniela Dirndorfer and Scarlett Dornauer for experimental help. This work was supported by the DFG (SFB 596 “Molecular Mechanisms of Neurodegeneration” to K.F.W., S.F.L., J.T., and W.W.), the BMBF (NGFN plus “Functional Genomics of Parkinson's Disease” to K.F.W. and W.W.), and the Helmholtz Alliance “Mental Health in an Ageing Society” (to K.F.W. and W.W.).
PY - 2013/3/7
Y1 - 2013/3/7
N2 - 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.
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.
UR - https://www.scopus.com/pages/publications/84876886863
U2 - 10.1016/j.molcel.2013.01.036
DO - 10.1016/j.molcel.2013.01.036
M3 - Article
C2 - 23453807
AN - SCOPUS:84876886863
SN - 1097-2765
VL - 49
SP - 908
EP - 921
JO - Molecular Cell
JF - Molecular Cell
IS - 5
ER -