Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress

• Published in: Cell death and differentiation Vol. 18; no. 5; pp. 769 - 782
• Main Authors: Bouman, L, Schlierf, A, Lutz, A K, Shan, J, Deinlein, A, Kast, J, Galehdar, Z, Palmisano, V, Patenge, N, Berg, D, Gasser, T, Augustin, R, Trümbach, D, Irrcher, I, Park, D S, Wurst, W, Kilberg, M S, Tatzelt, J, Winklhofer, K F
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2011; Nature Publishing Group
• Subjects: 631/208/200; 631/443/319/333; 692/699/375/365/1718; Activating Transcription Factor 4 - metabolism; Apoptosis; Basal ganglia; Base Sequence; Biochemistry; Biomedical and Life Sciences; c-Jun protein; Carbonyl Cyanide m-Chlorophenyl Hydrazone - pharmacology; Cell Biology; Cell Cycle Analysis; Cell Death; Cell Line; Cell survival; Central nervous system diseases; Cyclic AMP response element-binding protein; Disease; eIF-2 Kinase - metabolism; Endoplasmic reticulum; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - physiology; Enzyme Inhibitors - adverse effects; Genes, Reporter; Homeostasis; Humans; Ionophores - pharmacology; Kinases; Life Sciences; Luciferases, Renilla - biosynthesis; Membrane Potential, Mitochondrial; Mitochondria; Mitochondria - drug effects; Mitochondria - physiology; Movement disorders; Mutation; Neurodegeneration; Neurodegenerative diseases; Original Paper; Parkin protein; Parkinson's disease; Pathogenesis; Promoter Regions, Genetic; Promoters; Proteasome Endopeptidase Complex - physiology; proteasomes; Protein folding; Proteins; Proto-Oncogene Proteins c-jun - metabolism; Repressors; Response Elements - genetics; RNA Interference; Signal Transduction; Stem Cells; Stress; Stress, Physiological; Thapsigargin - adverse effects; Transcription factors; Transcription, Genetic; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Unfolded Protein Response; Up-Regulation; Germany; ER stress; c-Jun; Parkinson's disease; parkin; UPR; ATF4; mitochondria
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2010.142

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.