ER-stress-associated functional link between Parkin and DJ-1 via a transcriptional cascade involving the tumor suppressor p53 and the spliced X-box binding protein XBP-1.

Abstract

Parkin and DJ-1 are two multi-functional proteins linked to autosomal recessive early-onset Parkinson's disease (PD) that have been shown to functionally interact by as-yet-unknown mechanisms. We have delineated the mechanisms by which parkin controls DJ-1. Parkin modulates DJ-1 transcription and protein levels via a signaling cascade involving p53 and the endoplasmic reticulum (ER)-stress-induced active X-box-binding protein-1S (XBP-1S). Parkin triggers the transcriptional repression of p53 while p53 downregulates DJ-1 protein and mRNA expressions. We show that parkin-mediated control of DJ-1 is fully p53-dependent. Furthermore, we establish that p53 lowers the protein and mRNA levels of XBP-1S. Accordingly, we show that parkin ultimately upregulates XBP-1 levels. Subsequently, XBP-1S physically interacts with the DJ-1 promoter, thereby enhancing its promoter trans-activation, mRNA levels and protein expression. This data was corroborated by the examination of DJ-1 in both parkin- and p53-null mice brains. This transcriptional cascade is abolished by pathogenic parkin mutations and is independent of its ubiquitin-ligase activity. Our data establish a parkin-dependent ER-stress-associated modulation of DJ-1 and identifies p53 and XBP-1 as two major actors acting downstream of parkin in this signaling cascade in cells and in vivo. This work provides a mechanistic explanation for the increase in the unfolded protein response observed in PD pathology, i.e. that it is due to a defect in parkin-associated control of DJ-1.

• Authors: Eric Duplan, Emilie Giaime, Julien Viotti, Jean Sévalle, Olga Corti, Alexis Brice, Hiroyoshi Ariga, Ling Qi, Frédéric Checler, Cristine Alves da Costa
• Journal: Journal of cell science (J Cell Sci) Vol. 126 Issue Pt 9 Pg. 2124-33 (May 01 2013) ISSN: 1477-9137 [Electronic] England
• PMID: 23447676 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Intracellular Signaling Peptides and Proteins
• Oncogene Proteins
• Regulatory Factor X Transcription Factors
• TP53 protein, human
• Transcription Factors
• Tumor Suppressor Protein p53
• X-Box Binding Protein 1
• XBP1 protein, human
• Xbp1 protein, mouse
• Peroxiredoxins
• Ubiquitin-Protein Ligases
• parkin protein
• PARK7 protein, human
• PARK7 protein, mouse
• Protein Deglycase DJ-1

Topics

• Animals
• Cell Line, Tumor
• DNA-Binding Proteins (genetics, metabolism)
• Endoplasmic Reticulum Stress
• Gene Expression Regulation (genetics)
• HEK293 Cells
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Mice
• Mice, Mutant Strains (genetics)
• Oncogene Proteins (genetics, metabolism)
• Parkinson Disease (genetics, metabolism, pathology)
• Peroxiredoxins
• Protein Deglycase DJ-1
• Regulatory Factor X Transcription Factors
• Signal Transduction (genetics)
• Transcription Factors (genetics, metabolism)
• Transcription, Genetic
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• X-Box Binding Protein 1