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© The Rockefeller University Press, 0021-9525/1999//1195 $5.00
The Journal of Cell Biology, Volume 147, Number 6, , 1999 1195-1204

Original Article

Stress-Associated Endoplasmic Reticulum Protein 1 (Serp1)/Ribosome-Associated Membrane Protein 4 (Ramp4) Stabilizes Membrane Proteins during Stress and Facilitates Subsequent Glycosylation



Atsushi Yamaguchia,c, Osamu Horib,c, David M. Sternd, Enno Hartmanne, Satoshi Ogawab,c, and Masaya Tohyamaa,c

a Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita City, Osaka 565-0871, Japan
b Department of Anatomy III, Kanazawa University, School of Medicine, Kanazawa City, Ishikawa 290-8640, Japan
c Core Research for Evolutional Science and Technology, Japan Science and Technology, Tokyo 105, Japan
d Department of Surgery, Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York 10032
e Abteilung Biochemie II, Zentrum Biochemie und Moleculare Zellbiologie, Georg-August-Universität, 37073 Göttingen, Germany
Department of Anatomy III, Kanazawa University, Medical School, 13-1 Takara-Machi, Kanazawa City, Ishikawa 290-8640, Japan.81-76-234-422281-76-265-2162

osamuh{at}nanat.m.kanazawa-u.ac.jp

Application of differential display to cultured rat astrocytes subjected to hypoxia allowed cloning of a novel cDNA, termed stress-associated endoplasmic reticulum protein 1 (SERP1). Expression of SERP1 was enhanced in vitro by hypoxia and/or reoxygenation or other forms of stress, causing accumulation of unfolded proteins in endoplasmic reticulum (ER) stress, and in vivo by middle cerebral artery occlusion in rats. The SERP1 cDNA encodes a 66–amino acid polypeptide which was found to be identical to ribosome-associated membrane protein 4 (RAMP4) and bearing 29% identity to yeast suppressor of SecY 6 protein (YSY6p), suggesting participation in pathways controlling membrane protein biogenesis at ER. In cultured 293 cells subjected to ER stress, overexpression of SERP1/RAMP4 suppressed aggregation and/or degradation of newly synthesized integral membrane proteins, and subsequently, facilitated their glycosylation when the stress was removed. SERP1/RAMP4 interacted with Sec61{alpha} and Sec61β, which are subunits of translocon, and a molecular chaperon calnexin. Furthermore, Sec61{alpha} and Sec61β, but not SERP1/RAMP4, were found to associate with newly synthesized integral membrane proteins under stress. These results suggest that stabilization of membrane proteins in response to stress involves the concerted action of a rescue unit in the ER membrane comprised of SERP1/RAMP4, other components of translocon, and molecular chaperons in ER.

Key Words: hypoxia • endoplasmic reticulum stress • translocon • aggregation/degradation • refolding

© 1999 The Rockefeller University Press

A. Yamaguchi and O. Hori contributed equally to this work.

Abbreviations used in this paper: co-IP, coimmunoprecipitation; DSS, disuccinimidyl suberate; GRP, glucose-regulated protein; H, hypoxia; HA, hemagglutinin; HSP, heat shock protein; MCA, middle cerebral artery; ORF, open reading frame; ORP, oxygen-regulated protein; OST, oligosaccaryltransferase; PDI, protein disulfide isomerase; R, reoxygenation; RAGE, receptor for advanced glycation endproducts; RAMP, ribosome-associated membrane protein; SERP, stress-associated endoplasmic reticulum protein; YSY6p, yeast suppressor of SecY 6 protein.


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