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J. Biol. Chem., Vol. 280, Issue 28, 26622-26629, July 15, 2005

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Inefficient Maturation of the Rat Luteinizing Hormone Receptor

A PUTATIVE WAY TO REGULATE RECEPTOR NUMBERS AT THE CELL SURFACE^*

E. Maritta Pietilä, Jussi T. Tuusa, Pirjo M. Apaja, Jyrki T. Aatsinki, Anna E. Hakalahti, Hannu J. Rajaniemi, and Ulla E. Petäjä-Repo¶

From the Biocenter Oulu and Department of Anatomy and Cell Biology and the Department of Anatomy and Cell Biology, University of Oulu, FI-90014, Oulu, Finland

Increasing evidence suggests that the folding and maturation of monomeric proteins and assembly of multimeric protein complexes in the endoplasmic reticulum (ER) may be inefficient not only for mutants that carry changes in the primary structure but also for wild type proteins. In the present study, we demonstrate that the rat luteinizing hormone receptor, a G protein-coupled receptor, is one of these proteins that matures inefficiently and appears to be very prone to premature degradation. A substantial portion of the receptors in stably transfected human embryonic kidney 293 cells existed in immature form of M_r 73,000, containing high mannose-type N-linked glycans. In metabolic pulse-chase studies, only 20% of these receptor precursors were found to gain hormone binding ability and matured to a form of M_r 90,000, containing bi- and multiantennary sialylated N-linked glycans. The rest had a propensity to form disulfide-bonded complexes with a M_r 120,000 protein in the ER membrane and were eventually targeted for degradation in proteasomes. The number of membrane-bound receptor precursors increased when proteasomal degradation was inhibited, and no cytosolic receptor forms were detected, suggesting that retrotranslocation of the misfolded/incompletely folded receptors is tightly coupled to proteasomal function. Furthermore, a proteasomal blockade was found to increase the number of receptors that were capable of hormone binding. Thus, these results raise the interesting possibility that luteinizing hormone receptor expression at the cell surface may be controlled at the ER level by regulating the number of newly synthesized proteins that will mature and escape the ER quality control and premature degradation.

Received for publication, December 8, 2004 , and in revised form, May 2, 2005.

^* This work was supported by the Biocenter Oulu and a grant (200732) from the Academy of Finland. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ A research fellow of the Academy of Finland. To whom correspondence should be addressed: Dept. of Anatomy and Cell Biology, University of Oulu, P.O. Box 5000, FI-90014, Oulu, Finland. Tel.: 358-8-537-5193; Fax: 358-8-537-5172; E-mail: Ulla.Petaja-Repo{at}oulu.fi.

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