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. 1999 Dec 13;147(6):1195-204.
doi: 10.1083/jcb.147.6.1195.

Stress-associated endoplasmic reticulum protein 1 (SERP1)/Ribosome-associated membrane protein 4 (RAMP4) stabilizes membrane proteins during stress and facilitates subsequent glycosylation

A Yamaguchi  1 , O Hori, D M Stern, E Hartmann, S Ogawa, M Tohyama
Affiliations

Stress-associated endoplasmic reticulum protein 1 (SERP1)/Ribosome-associated membrane protein 4 (RAMP4) stabilizes membrane proteins during stress and facilitates subsequent glycosylation

A Yamaguchi et al. J Cell Biol. .

Abstract

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 Sec61alpha and Sec61beta, which are subunits of translocon, and a molecular chaperon calnexin. Furthermore, Sec61alpha and Sec61beta, 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.

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Figures

Figure 1
Figure 1
Amino acid sequence of rat and human SERP1. The putative transmembrane domain is underlined and the sequence used for raising antibodies is indicated by the box.
Figure 3
Figure 3
Immunostaining of BHK cells transfected with the FLAG-tagged pcDNA/SERP1/RAMP4 using anti-FLAG antibody (a), anti-PDI antibody (b), and both (c). SERP1/RAMP4-transfected BHK cells were fixed in 0.1% NP-40/4% paraformaldehyde solution and subjected to the immunostaining protocol (see text). Sites of primary antibody binding were visualized with TRITC-conjugated anti–mouse antibody for FLAG epitope (a), FITC conjugated anti–rabbit antibody for PDI (b), or using both detection systems (c). Upper panels show lower magnification and lower panels higher magnification. Note that the two epitopes colocalize throughout the interior, and even in peripheral regions of the cells.
Figure 4
Figure 4
Expression of SERP1/RAMP4 in ischemic rat brain. Brain ischemia was induced in rats by unilateral (left) MCA occlusion. After 12 h of ischemia, rats were killed and brain slices were studied by in situ hybridization (a and b) with riboprobes derived from SERP1 cDNA to detect SERP1/RAMP4 transcripts. SERP1/RAMP4 antigen was also studied with the homogenates of the same brain samples using immunoprecipitation followed by Western blotting with anti–SERP1/RAMP4 antibody (c). b shows a microautoradiogram of boxed area in a, displaying enhanced SERP1/RAMP4 mRNA in the periischemic penumbral region. c shows the induction of SERP1/RAMP4 at the protein level in ischemic brain. C, control hemisphere; I, ischemic hemisphere. Migration of simultaneously run molecular mass standards is indicated on the left side in kD. Quantification of SERP1/RAMP4 antigen in ischemic brain (c, right) was showed as fold increase (mean ± SD of three experiments).
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