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N-Linked Oligosaccharides Direct the Differential Assembly and Secretion of Inhibin - and ß_A-Subunit Dimers

Department of Neurobiology and Physiology (M.A., M.S., T.K.W.), Northwestern University, Evanston, Illinois 60208; Department of Molecular Biology and Pharmacology (I.B.), Washington University School of Medicine, St. Louis, Missouri 63110; Department of Medicine (T.K.W.), Northwestern University Medical School, Chicago, Illinois 60611; and Robert H. Lurie Comprehensive Cancer Center of Northwestern University (T.K.W.), Chicago, Illinois 60611

Address all correspondence and requests for reprints to: Teresa K. Woodruff, Ph.D., Department of Neurobiology and Physiology, Northwestern University, O. T. Hogan 4-150, 2205 Tech Drive, Evanston, Illinois 60208. E-mail: tkw{at}northwestern.edu.

The biosynthetic pathway governing inhibin heterodimer (/ß) and activin homodimer (ß/ß) assembly and secretion from ovarian granulosa cells is not fully understood. Here, we examined the role of inhibin subunit glycosylation in the assembly and secretion of mature inhibin A and activin A. Inhibition of subunit glycosylation by tunicamycin treatment of - and ß_A-expressing CHO cell lines reduced inhibin but not activin secretion. Dimeric inhibin A is preferentially secreted from parental isogenic wild-type (wt) cell lines (^wtß^wt). Mutation of a single glycosylation site at asparagine 268 (²⁶⁸ß^wt) reduces inhibin secretion by 78% and permits ß/ß assembly and secretion. Conversely, gain of a glycosylation (GOG) site in the analogous region of the ß_A-subunit (^wtß^GOG327) enhances inhibin A secretion. The present study demonstrates that N-linked glycan sites direct heterodimer vs. homodimer assembly, and prevention of glycosylation abrogates inhibin secretion. These data support a definitive role for site-specific N-glycosylation in governing inhibin/activin dimer assembly and secretion.

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