Cellular and Molecular NeuroscienceResearch PaperThe KDEL receptor induces autophagy to promote the clearance of 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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