title: Translational up-regulation of polycystic kidney disease protein PKD2 by endoplasmic reticulum stress.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2, and it affects over 10 million people worldwide. It is characterized by cyst formation in the kidney, liver and pancreas. Dosage changes in PKD1/PKD2 are important in ADPKD pathogenesis; therefore, their expression and function has to be strictly regulated. However, how they are regulated remain poorly understood. Recent studies have linked PKD2 regulation to endoplasmic reticulum (ER) stress that is implicated in neuronal, cardiac, and renal diseases. One major ER stress downstream is phosphorylation of eukaryotic initiation factor eIF2α by kinase PERK, which attenuates global protein translation and enhances translation of selected proteins. Here, we showed in several mammalian cell lines that PKD2 protein expression is up-regulated by different stresses that all increase phosphorylated eIF2α (P-eIF2α). Increasing P-eIF2α by overexpression or inhibiting the phosphatase activity resulted in increased PKD2. PCR and polysome-binding assays showed that ER stress does not affect the PKD2 mRNA level but increase its binding with ribosomes, indicating that P-eIF2α translationally up-regulates PKD2. By mutation analysis, we found that the upstream open reading frame (uORF) in the 5'-untranslated region of PKD2 mRNA represses PKD2 translation. Thus, ER stress and P-eIF2α translationally up-regulates PKD2 through bypassing the inhibitory uORF.
authors.affiliation: 2Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, 7-29 Medical Sciences Bldg., Edmonton, AB T6G 2H7, Canada. xzchen@ualberta.ca.
authors.forename: Jungwoo
authors.initials: J
authors.lastname: Yang
authors.forename: Wang
authors.initials: W
authors.lastname: Zheng
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Carlos
authors.initials: C
authors.lastname: Lara
authors.forename: Shaimaa
authors.initials: S
authors.lastname: Hussein
authors.forename: Xing-Zhen
authors.initials: XZ
authors.lastname: Chen
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D004285:Dogs; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D009154:Mutation; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050396:TRPP Cation Channels / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation
chemical_list: D020121:5' Untranslated Regions; D015852:Eukaryotic Initiation Factor-2; D012333:RNA, Messenger; D050396:TRPP Cation Channels
keywords: ADPKD; P-eIF2α; uORF