Role of Selenof as a Gatekeeper of Secreted Disulfide-Rich Glycoproteins

Authors

• Sun Hee Yim, Brigham and Women's Hospital and Harvard Medical School
• Robert A. Everley, Harvard Medical School
• Frank A. Schildberg, Harvard Medical School
• Sang-Goo Lee, Brigham and Women's Hospital and Harvard Medical School
• Andrea Orsi, IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milano, Italy
• Zachary R. Barbati, Harvard Medical School
• Kutay Karatepe, Harvard Medical School
• Dmitri E. Fomenko, University of Nebraska-LincolnFollow
• Petra A. Tsuji, Towson University
• Hongbo R. Luo, Harvard Medical School
• Steven P. Gygi, Harvard Medical School
• Roberto Sitia, IRCCS Ospedale San Raffaele and Universita` Vita-Salute San Raffaele, Milano, Italy
• Arlene H. Sharpe, Harvard Medical School
• Dolph L. Hatfield, National Institutes of HealthFollow
• Vadim N. Gladyshev, Brigham and Women's Hospital and Harvard Medical SchoolFollow

Document Type

Article

Date of this Version

5-1-2018

Citation

Cell Reports 23, 1387–1398, May 1, 2018

Comments

This is an open access article under the CC BY-NC-ND license

Abstract

Selenof (15-kDa selenoprotein; Sep15) is an endoplasmic reticulum (ER)-resident thioredoxin-like oxidoreductase that occurs in a complex with UDPglucose: glycoprotein glucosyltransferase. We found that Selenof deficiency in mice leads to elevated levels of non-functional circulating plasma immunoglobulins and increased secretion of IgM during in vitro splenic B cell differentiation. However, Selenof knockout animals show neither enhanced bacterial killing capacity nor antigen-induced systemic IgM activity, suggesting that excess immunoglobulins are not functional. In addition, ER-to-Golgi transport of a target glycoprotein was delayed in Selenof knockout embryonic fibroblasts, and proteomic analyses revealed that Selenof deficiency is primarily associated with antigen presentation and ER-to-Golgi transport. Together, the data suggest that Selenof functions as a gatekeeper of immunoglobulins and, likely, other client proteins that exit the ER, thereby supporting redox quality control of these proteins.