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

Konstanze F. Winklhofer (1) , Lena Bouman (1) , Anita Schlierf (1) , A. Kathrin Lutz (1) , Jixiu Shan (1) , Alexandra Deinlein (1) , Jessica Kast (1) , Zohreh Galehdar (1) , Vincenza Palmisano (1) , Nadja Patenge (1) , Daniela Berg (1) , Thomas Gasser (1) , Regina Augustin (1) , Dietrich Trümbach (1) , Isabella Irrcher (1) , David S Park (1) , Wolfgang Wurst (1) , Michael S. Kilberg (1) , Jörg Tatzelt (1)

1 Biochemistry

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 up-regulation 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 up-regulation 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 cyto-protective activity of parkin. Our study supports the notion that parkin plays 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.

Mots clés: parkin; ATF4; ER stress; UPR; mitochondria

Konstanze F. Winklhofer, Lena Bouman, Anita Schlierf, A. Kathrin Lutz, Jixiu Shan, et al.. Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. Cell Death and Differentiation, 2010, ⟨10.1038/cdd.2010.142⟩. ⟨hal-00595932⟩