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Misfolded growth hormone causes fragmentation of the Golgi apparatus and disrupts endoplasmic reticulum-to-Golgi traffic

¹ Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
² Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA

*Author for correspondence (patricia_hinkle{at}urmc.rochester.edu)

Accepted July 9, 2001

In some individuals with autosomal dominant isolated growth hormone deficiency, one copy of growth hormone lacks amino acids 32-71 and is severely misfolded. We transfected COS7 cells with either wild-type human growth hormone or 32-71 growth hormone and investigated subcellular localization of growth hormone and other proteins. 32-71 growth hormone was retained in the endoplasmic reticulum, whereas wild-type hormone accumulated in the Golgi apparatus. When cells transfected with wild-type or 32-71 growth hormone were dually stained for growth hormone and the Golgi markers ß-COP, membrin or 58K, wild-type growth hormone was colocalized with the Golgi markers, but ß-COP, membrin and 58K immunoreactivity was highly dispersed or undetectable in cells expressing 32-71 growth hormone. Examination of -tubulin immunostaining showed that the cytoplasmic microtubular arrangement was normal in cells expressing wild-type growth hormone, but microtubule-organizing centers were absent in nearly all cells expressing 32-71 growth hormone. To determine whether 32-71 growth hormone would alter trafficking of a plasma membrane protein, we cotransfected the cells with the thyrotropin-releasing hormone (TRH) receptor and either wild-type or 32-71 growth hormone. Cells expressing 32-71 growth hormone, unlike those expressing wild-type growth hormone, failed to show normal TRH receptor localization or binding. Expression of 32-71 growth hormone also disrupted the trafficking of two secretory proteins, prolactin and secreted alkaline phosphatase. 32-71 growth hormone only weakly elicited the unfolded protein response as indicated by induction of BiP mRNA. Pharmacological induction of the unfolded protein response partially prevented deletion mutant-induced Golgi fragmentation and partially restored normal TRH receptor trafficking. The ability of some misfolded proteins to block endoplasmic reticulum-to-Golgi traffic may explain their toxic effects on host cells and suggests possible strategies for therapeutic interventions.

Key words: Golgi apparatus, Growth hormone, Unfolded protein response

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