Roles of the 15-kDa Selenoprotein (Sep15) in Redox Homeostasis and Cataract Development Revealed by the Analysis of Sep 15 Knockout Mice

Authors

Marina V. Kasaikina, University of Nebraska-LincolnFollow
Dmitri E. Fomenko, University of Nebraska - LincolnFollow
Vyacheslav M. Labunskyy, Brigham and Women’s Hospital and Harvard Medical School
Salil A. Lachke, Brigham and Women’s Hospital and Harvard Medical School
Wenya Qiu, University of Nebraska, Lincoln
Juliet A. Moncaster, Boston University School of Medicine
Jie Zhang, Charite´-Universita¨tsmedizin Berlin
Mark W. Wojnarowicz, Boston University School of Medicine- Boston
Sathish Kumar Natarajan, University of Nebraska-LincolnFollow
Mikalai I. Malinouski, University of Nebraska - LincolnFollow
Ulrich Schweizer, Neurobiology of Selenium, Neuroscience Research Center, Charite-Universitatsmedizin, 10117 Berlin, Germany
Petra A. Tsuji, Towson UniversityFollow
Bradley A. Carlson, Laboratory of Cancer Prevention, CCR, NCI, NIH, Bethesda, MD
Richard L. Maas, Brigham and Women’s Hospital and Harvard Medical School
Marjorie F. Lou, University of Nebraska-LincolnFollow
Lee E. Goldstein, Boston University School of Medicine
Dolph L. Hatfield, Laboratory of Cancer Prevention, CCR, NCI, NIH, Bethesda, MDFollow
Vadim N. Gladyshev, Brigham & Women’s Hospital and Harvard Medical SchoolFollow

Document Type

Article

Date of this Version

2011

Citation

THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 286, NO. 38, pp. 33203–33212, September 23, 2011

Comments

© 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

Abstract

The 15-kDa selenoprotein (Sep15) is a thioredoxin-like, endoplasmic reticulum-resident protein involved in the quality control of glycoprotein folding through its interaction with UDP-glucose:glycoprotein glucosyltransferase. Expression of Sep15 is regulated by dietary selenium and the unfolded protein response, but its specific function is not known. In this study, we developed and characterized Sep15 KO mice by targeted removal of exon 2 of the Sep15 gene coding for the cysteinerich UDP-glucose:glycoprotein glucosyltransferase-binding domain. These KO mice synthesized a mutant mRNA, but the shortened protein product could be detected neither in tissues nor in Sep15 KO embryonic fibroblasts. Sep15 KO mice were viable and fertile, showed normal brain morphology, and did not activate endoplasmic reticulum stress pathways. However, parameters of oxidative stress were elevated in the livers of these mice. We found that Sep15 mRNA was enriched during lens development. Further phenotypic characterization of Sep15KO mice revealed a prominent nuclear cataract that developed at an early age. These cataracts did not appear to be associated with severe oxidative stress or glucose dysregulation.Wesuggest that the cataracts resulted from an improper folding status of lens proteins caused by Sep15 deficiency.