Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress.
Loss of parkin function is responsible for the majority of autosomal recessive parkinsonism. Here, we show that parkin is not only a stress-protective, but also a stress-inducible protein. Both mitochondrial and endoplasmic reticulum (ER) stress induce an increase in parkin-specific mRNA and protein levels. The stress-induced upregulation of parkin is mediated by ATF4, a transcription factor of the unfolded protein response (UPR) that binds to a specific CREB/ATF site within the parkin promoter. Interestingly, c-Jun can bind to the same site, but acts as a transcriptional repressor of parkin gene expression. We also present evidence that mitochondrial damage can induce ER stress, leading to the activation of the UPR, and thereby to an upregulation of parkin expression. Vice versa, ER stress results in mitochondrial damage, which can be prevented by parkin. Notably, the activity of parkin to protect cells from stress-induced cell death is independent of the proteasome, indicating that proteasomal degradation of parkin substrates cannot explain the cytoprotective activity of parkin. Our study supports the notion that parkin has a role in the interorganellar crosstalk between the ER and mitochondria to promote cell survival under stress, suggesting that both ER and mitochondrial stress can contribute to the pathogenesis of Parkinson's disease.
Adolf Butenandt Institute, Neurobiochemistry, Ludwig Maximilians University, Schillerstrasse 44, Munich, Germany.
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Bouman
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Schlierf
A K
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Lutz
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J
Shan
A
A
Deinlein
J
J
Kast
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Galehdar
V
V
Palmisano
N
N
Patenge
D
D
Berg
T
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Gasser
R
R
Augustin
D
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Trümbach
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Irrcher
D S
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Park
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Wurst
M S
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Kilberg
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Tatzelt
K F
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Winklhofer
D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D001483:Base Sequence; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D016923:Cell Death; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000009:adverse effects; D017930:Genes, Reporter; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D049410:Luciferases, Renilla / Q000096:biosynthesis; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034622:RNA Interference; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction; D013312:Stress, Physiological; D019284:Thapsigargin / Q000009:adverse effects; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D056811:Unfolded Protein Response; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000378:metabolism
D051701:Activating Transcription Factor 4; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D004791:Enzyme Inhibitors; D007476:Ionophores; D049410:Luciferases, Renilla; D046988:Proteasome Endopeptidase Complex; D016755:Proto-Oncogene Proteins c-jun; D019284:Thapsigargin; D044767:Ubiquitin-Protein Ligases; D019892:eIF-2 Kinase; C497109:ATF4 protein, human; C111567:parkin protein