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

SummaryParkin 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)-stressinduced 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 parkindependent 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.

UPR, autophagy, and mitochondria crosstalk underlies the ER stress response

“…UPR transducers affect mitochondrial regulatory components, including ATF4, which was demonstrated to control expression of the ubiquitin ligase Parkin, a crucial regulator of mitochondria function and dynamics [27]. In turn, reciprocal activation is illustrated by the ability of Parkin to enhance select branches of the UPR signaling through the activation of the sXBP1 pathway [28]. ATF6 is also associated with the activation of PCG1α (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha), a master regulator of mitochondrial biogenesis, thereby linking the UPR with metabolic gene programs [29].…”

Endoplasmic Reticulum Stress–Activated Cell Reprogramming in Oncogenesis

“…ATM-defi cient cells undergo hyperactivation of IRE1 when exposed to ionizing radiation ( 119 ), and both p53-defi cient cells and ATM-defi cient cells develop spontaneous alterations in ER proteostasis (119)(120)(121). Cross-talk between the UPR and p53 has been reported in many studies (see examples in refs.…”

Tumor Suppressor Genes within Common Fragile Sites Are Active Players in the DNA Damage Response

“…It modulates PARK7 (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). In a negative feedback loop, PARK2 triggers transcriptional repression of p53 while p53 down-regulates expression of PARK7 protein and mRNA [119]. …”