Elsevier

Neuroscience

Volume 190, 5 September 2011, Pages 43-55
Neuroscience

Cellular and Molecular Neuroscience
Research Paper
The KDEL receptor induces autophagy to promote the clearance of neurodegenerative disease-related proteins

https://doi.org/10.1016/j.neuroscience.2011.06.008Get rights and content

Abstract

Endoplasmic reticulum (ER) stress is involved in neurodegenerative diseases, and the KDEL (Lys-Asp-Glu-Leu motif) receptor (KDELR) plays a key role in ER quality control and in the ER stress response. The subcellular distribution of KDELR is dynamic and related to its ligand binding status and its expression level. Here, we show that KDELR mRNA is upregulated upon thapsigargin treatment, which induces ER stress. Moreover, overexpressed KDELR partially redistributes to the lysosome and activates autophagy. The R169N mutant, a ligand binding-defective form of KDELR, and D193N, a transport-defective form of KDELR, both fail to trigger autophagy. Overexpression of KDELR activates extracellular signal-regulated kinases (ERKs). Both the activation of ERKs and autophagy induced by KDELR could be blocked by PD98059, an inhibitor of mitogen extracellular kinase 1 (MEK1). The overexpression of some neurodegenerative disease-related proteins, such as amyotrophic lateral sclerosis (ALS)-linked G93A superoxide dismutase 1 (SOD1), Parkinson's disease-associated A53T alpha-synuclein and Huntington's disease-related expanded huntingtin, increase the mRNA levels of KDELR. Moreover, the overexpressed KDELR promotes the clearance of these disease proteins through autophagy. Taken together, our data provide evidence that KDELR, as a novel inducer of autophagy, participates in the degradation of misfolded neurodegenerative disease-related proteins.

Highlights

▶ER stress upregulates the KDEL receptor levels. ▶Overexpression of the KDEL receptor activates ERKs to induce autophagy. ▶The KDEL receptor mutants fail to induce autophagy. ▶The KDEL receptor promotes the clearance of neurodegenerative disease-related proteins.

Section snippets

Plasmid construction

The Myc-tagged full-length KDELR plasmids were kindly shared by Dr. Victor Hsu (Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA). KDELR cDNA was amplified by PCR with the primers 5′-GCAGGATCCCCATGAATCTCTTCCGATTCCTGG-3′ and 5′-GATCTCGAGTGCCGGCAAACTCAACTTCTTCCC-3′ and then inserted in-frame into pEGFP-N3 (Clontech Laboratories, Palo Alto, CA, USA) and p3xFlag-CMV-myc-24 (Sigma, St. Louis, MO, USA) plasmids. The plasmid pKH3-KDELR was obtained by excising KDELR cDNA from

Upregulation of KDELR under ER stress

It has been reported that KDELR participates in the ER stress response and is upregulated under ER stress in yeast and plants (Bar-Peled et al., 1995, Travers et al., 2000, Yamamoto et al., 2003). We therefore used RT-PCR to detect the level of KDELR mRNA. In HeLa cells treated with the ER stress inducer TG, the mRNA level of CHOP, a downstream product of the ER stress response, was upregulated (Fig. 1A, B). Meanwhile in mammalian HeLa cells, KDELR was significantly upregulated (Fig. 1A, C),

Discussion

An impairment of ER quality control will result in the accumulation of misfolded proteins in the ER and evoke an ER stress response. As a result, a series of cellular processes will be triggered to protect or kill these cells. KDELR not only plays a role in ER quality control, but also participates in the ER stress response (Yamamoto et al., 2001, Yamamoto et al., 2003). Many chaperones bearing the KDEL sequence are finely regulated by ER stress; meanwhile, KDELR is also upregulated in yeast

Conclusion

In summary, our study shows that KDELR is upregulated under ER stress and that the overexpression of KDELR activates ERKs to induce autophagy, thereby promoting the clearance of neurodegenerative disease proteins. Our work thus implies that KDELR may have a role in protein degradation in association with the induction of autophagy.

Acknowledgments

We are grateful to Dr. Victor Hsu (Brigham and Women's Hospital/Harvard Medical School) for KDELR expression plasmids and to Dr. Noboru Mizushima (Tokyo Medical and Dental University, Japan) for ATG5 WT and KO MEF cells. This work was supported in part by the National Natural Sciences Foundation of China (Nos. 30970921 and 30900412), the National High-tech Research and Development program of China 973-projects (2011CB5004102), and the special grade of the financial support from China

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