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Sci Rep. 2017 Sep 13;7(1):11493. doi: 10.1038/s41598-017-11526-0.

Polycystin-1 inhibits eIF2α phosphorylation and cell apoptosis through a PKR-eIF2α pathway.

Author information

1
Department of Oncology and Haematology, The Second Hospital, Jilin University, 130041, Changchun, Jilin, China.
2
Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, T6G 2H7, Edmonton, AB, Canada.
3
Division of Translational Cancer Research and Therapy, State Key Laboratory of Molecular Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
4
Department of Medicine, Vanderbilt University, TN 37232, Nashville, Tennessee, USA.
5
Academic Department of Medical Genetics, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, CB2 0QQ, Cambridge, Cambridge, UK.
6
Institute of Biomedical and Pharmaceutical Sciences, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, 430068, Wuhan, Hubei, China. jingfeng9930@163.com.
7
Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, T6G 2H7, Edmonton, AB, Canada. xzchen@ualberta.ca.
8
Institute of Biomedical and Pharmaceutical Sciences, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, 430068, Wuhan, Hubei, China. xzchen@ualberta.ca.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2 which encodes polycystin-1 (PC1) and polycystin-2, respectively. PC1 was previously shown to slow cell proliferation and inhibit apoptosis but the underlying mechanisms remain elusive or controversial. Here we showed in cultured mammalian cells and Pkd1 knockout mouse kidney epithelial cells that PC1 and its truncation mutant comprising the last five transmembrane segments and the intracellular C-terminus (PC1-5TMC) down-regulate the phosphorylation of protein kinase R (PKR) and its substrate eukaryotic translation initiation factor 2 alpha (eIF2α). PKR is known to be activated by interferons and dsRNAs, inhibits protein synthesis and induces apoptosis. By co-immunoprecipitation experiments we found that PC1 truncation mutants associate with PKR, or with PKR and its activator PACT. Further experiments showed that PC1 and PC1-5TMC reduce phosphorylation of eIF2α through inhibiting PKR phosphorylation. Our TUNEL experiments using tunicamycin, an apoptosis inducer, and GADD34, an inhibitor of eIF2α phosphorylation, demonstrated that PC1-5TMC inhibits apoptosis of HEK293T cells in a PKR-eIF2α-dependent manner, with concurrent up- and down-regulation of Bcl-2 and Bax, respectively, revealed by Western blotting. Involvement of PC1-regulated eIF2α phosphorylation and a PKR-eIF2α pathway in cell apoptosis may be an important part of the mechanism underlying ADPKD pathogenesis.

PMID:
28904368
PMCID:
PMC5597606
DOI:
10.1038/s41598-017-11526-0
[Indexed for MEDLINE]
Free PMC Article

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