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

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.