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Original Article |
Correspondence to: Osamu Hori, Department of Anatomy III, Kanazawa University, Medical School, 13-1 Takara-Machi, Kanazawa City, Ishikawa 290-8640, Japan. Tel:81-76-265-2162 Fax:81-76-234-4222 E-mail: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
and Sec61ß, which are subunits of translocon, and a molecular chaperon calnexin. Furthermore, Sec61 and Sec61ß, 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
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