Vaspin is an adipokine ameliorating ER stress in obesity as a ligand for cell-surface GRP78/MTJ-1 complex.
Vaspin is an adipokine ameliorating ER stress in obesity as a ligand for cell-surface GRP78/MTJ-1 complex.
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作者：
Nakatsuka A;Wada J;Iseda I;Teshigawara S;Higashio K;Murakami K;Kanzaki M;Inoue K;Terami T;Katayama A;Hida K;Eguchi J;Horiguchi CS;Ogawa D;Matsuki Y;Hiramatsu R;Yagita H;Kakuta S;Iwakura Y;Makino H
目前尚不清楚来自脂肪组织的脂肪因子是否调节肥胖引起的内质网应激。在这里，我们发现内脏脂肪组织来源的丝氨酸蛋白酶抑制剂（vaspin）与细胞表面78 kda葡萄糖调节蛋白（GRP78）结合，该蛋白在内质网应激下从内质网募集到质膜。Vaspin转基因小鼠免受饮食诱导的肥胖、葡萄糖耐受不良和肝脂肪变性的影响，而Vaspin缺乏小鼠则出现与内质网应激标志物上调相关的葡萄糖耐受不良。通过HepG2细胞的串联亲和标签纯化，我们鉴定出GRP78是一个相互作用分子。用生物素和免疫沉淀法对肝组织和H-4-II-E-C3细胞进行细胞表面标记，证实了vaspin、GRP78和小鼠肿瘤细胞DnaJ样蛋白1 (MTJ-1) （DnaJ同源物，C亚家族，成员1）在质膜上形成复合物。在培养的H-4-II-E-C3细胞中加入重组人vaspin也以剂量依赖的方式增加了Akt和amp活化蛋白激酶（AMPK）的磷酸化，抗grp78抗体完全消除了vaspin诱导的pAkt和pAMPK的上调。Vaspin是细胞表面GRP78/MTJ-1复合物的新型配体，其后续信号在内质网应激诱导的代谢功能障碍中发挥有益作用。
It is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue–derived serine protease inhibitor (vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose-dependent manner, and anti-GRP78 antibodies completely abrogated the vaspin-induced upregulation of pAkt and pAMPK. Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress–induced metabolic dysfunctions.
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3.7
作者：
Zhang Y;Wada J;Yasuhara A;Iseda I;Eguchi J;Fukui K;Yang Q;Yamagata K;Hiesberger T;Igarashi P;Zhang H;Wang H;Akagi S;Kanwar YS;Makino H
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