Cell surface expression of CD147/EMMPRIN is regulated by cyclophilin 60
Cell surface expression of CD147/EMMPRIN is regulated by cyclophilin 60
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DOI：
10.1074/jbc.m503770200
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发表时间：
2005-07-29
影响因子：
4.8
通讯作者：
Bukrinsky, MI
中科院分区：
文献类型：
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作者：
Pushkarsky, T;Yurchenko, V;Bukrinsky, MI
CD147，也称为细胞外基质金属蛋白酶诱导剂，是基质金属蛋白酶产生的调节剂，也是细胞外亲环蛋白的信号传导受体。此前，我们证明CD147的细胞表面表达对亲环蛋白结合药物环孢菌素A敏感，表明亲环蛋白参与CD147细胞内转运的调节。在本报告中，我们将这种亲环蛋白鉴定为亲环蛋白 60 (Cyp60)，它是亲环蛋白家族的一个独特成员。 CD147 与 Cyp60 共免疫沉淀，共聚焦免疫荧光显微镜显示 Cyp60 和 CD147 的细胞内共定位。这种与 Cyp60 的相互作用涉及 CD147 的脯氨酸 211，先前已证明脯氨酸对于溶液中 CD147 与另一种亲环蛋白（亲环蛋白 A）之间的相互作用至关重要。该脯氨酸残基的突变消除了 CD147 和 Cyp60 的免疫共沉淀，并减少了 CD147 在质膜上的表面表达。使用 RNA 干扰抑制 Cyp60 表达具有与环孢菌素 A 类似的效果：减少细胞表面 CD147 的表达。这些结果表明 Cyp60 在 CD147 易位至细胞表面中发挥重要作用。因此，Cyp60可能为CD147作为致病因素的疾病（例如癌症、人类免疫缺陷病毒感染或类风湿性关节炎）的治疗干预提供新的靶点。
CD147, also known as extracellular matrix metalloproteinase inducer, is a regulator of matrix metalloproteinase production and also serves as a signaling receptor for extracellular cyclophilins. Previously, we demonstrated that cell surface expression of CD147 is sensitive to cyclophilin-binding drug cyclosporin A, suggesting involvement of a cyclophilin in the regulation of intracellular transport of CD147. In this report, we identify this cyclophilin as cyclophilin 60 (Cyp60), a distinct member of the cyclophilin family of proteins. CD147 co-immunoprecipitated with Cyp60, and confocal immunofluorescent microscopy revealed intracellular colocalization of Cyp60 and CD147. This interaction with Cyp60 involved proline 211 of CD147, which was shown previously to be critical for interaction between CD147 and another cyclophilin, cyclophilin A, in solution. Mutation of this proline residue abrogated co-immunoprecipitation of CD147 and Cyp60 and reduced surface expression of CD147 on the plasma membrane. Suppression of Cyp60 expression using RNA interference had an effect similar to that of cyclosporin A: reduction of cell surface expression of CD147. These results suggest that Cyp60 plays an important role in the translocation of CD147 to the cell surface. Therefore, Cyp60 may present a novel target for therapeutic interventions in diseases where CD147 functions as a pathogenic factor, such as cancer, human immunodeficiency virus infection, or rheumatoid arthritis.