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

Authors

Sun Hee Yim, Harvard Medical School
Robert A. Everley, Harvard Medical School
Frank A. Schildberg, Harvard Medical School
Sang-Goo Lee, Harvard Medical School
Andrea Orsi, Universita Vita-Salute San Raffaele
Zachary R. Barbati, Harvard Medical School
Kutay Karatepe, Harvard Medical School
Dmitry E. Fomenko, University of Nebraska - Lincoln
Petra A. Tsuji, Towson University
Hongbo R. Luo, Harvard Medical School
Steven P. Gygi, Harvard Medical School
Roberto Sitia, Universita Vita-Salute San Raffaele
Arlene H. Sharpe, Harvard Medical School
Dolph L. Hatfield, National Cancer InstituteFollow
Vadim N. Gladyshev, Harvard Medical SchoolFollow

Document Type

Article

Date of this Version

2018

Citation

Cell Reports 23, 1387–1398

Comments

© 2018 The Author(s).

Open access

https://doi.org/10.1016/j.celrep.2018.04.009

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.