Tetraspanin CD9 modulates ADAM17-mediated shedding of LR11 in leukocytes.
Tetraspanin CD9 modulates ADAM17-mediated shedding of LR11 in leukocytes.
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DOI：
10.1038/emm.2013.161
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发表时间：
2014-04-04
影响因子：
12.8
通讯作者：
Nakaseko, Chiaki
中科院分区：
文献类型：
--
作者：
Tsukamoto, Shokichi;Takeuchi, Masahiro;Kawaguchi, Takeharu;Togasaki, Emi;Yamazaki, Atsuko;Sugita, Yasumasa;Muto, Tomoya;Sakai, Shio;Takeda, Yusuke;Ohwada, Chikako;Sakaida, Emiko;Shimizu, Naomi;Nishii, Keigo;Jiang, Meizi;Yokote, Koutaro;Bujo, Hideaki;Nakaseko, Chiaki
LR11，也称为 SorLA 或 SORL1，是一种 I 型膜蛋白，其中一个大的细胞外部分，可溶性 LR11 (sLR11)，通过解整合素和金属蛋白酶 17 (ADAM17) 裂解时的蛋白水解脱落而释放。据推测，脱落机制在 LR11 的功能中发挥着关键作用，但尚未证实这一点的证据。最近显示，四跨膜蛋白 CD9 可以调节 ADAM17 介导的细胞表面肿瘤坏死因子-α 和细胞间粘附分子-1 的脱落。在这里，我们研究了 CD9 对白细胞中 LR11 脱落的作用。 LR11 在 THP-1 单核细胞中不表达，但在佛波醇 12-肉豆蔻酸酯 13-乙酸酯 (PMA) 诱导的 THP-1 巨噬细胞 (PMA/THP-1) 中表达和释放。共聚焦显微镜显示 LR11 和 CD9 蛋白共定位于 PMA/THP-1 的细胞表面。 CCRF-SB 细胞（LR11 阳性和 CD9 阴性）中 CD9 的异位新表达减少了细胞释放的 sLR11 量。相反，将 LR11 转染的 THP-1 细胞与中和抗 CD9 单克隆抗体一起孵育会增加细胞释放的 sLR11 量。同样，在转染 CD9 靶向 shRNA 的 THP-1 细胞中，PMA 刺激的 sLR11 释放增加，但通过金属蛋白酶抑制剂 GM6001 处理可以消除这种情况。这些结果表明，四跨膜蛋白 CD9 在各种白血病细胞系中调节 ADAM17 介导的 LR11 脱落，并且细胞表面上 LR11 和 CD9 之间的关联在 ADAM17 介导的脱落机制中具有重要作用。
LR11, also known as SorLA or SORL1, is a type-I membrane protein from which a large extracellular part, soluble LR11 (sLR11), is released by proteolytic shedding on cleavage with a disintegrin and metalloproteinase 17 (ADAM17). A shedding mechanism is presumed to have a key role in the functions of LR11, but the evidence for this has not yet been demonstrated. Tetraspanin CD9 has been recently shown to regulate the ADAM17-mediated shedding of tumor necrosis factor-α and intercellular adhesion molecule-1 on the cell surface. Here, we investigated the role of CD9 on the shedding of LR11 in leukocytes. LR11 was not expressed in THP-1 monocytes, but it was expressed and released in phorbol 12-myristate 13-acetate (PMA)-induced THP-1 macrophages (PMA/THP-1). Confocal microscopy showed colocalization of LR11 and CD9 proteins on the cell surface of PMA/THP-1. Ectopic neo-expression of CD9 in CCRF-SB cells, which are LR11-positive and CD9-negative, reduced the amount of sLR11 released from the cells. In contrast, incubation of LR11-transfected THP-1 cells with neutralizing anti-CD9 monoclonal antibodies increased the amount of sLR11 released from the cells. Likewise, the PMA-stimulated release of sLR11 increased in THP-1 cells transfected with CD9-targeted shRNAs, which was negated by treatment with the metalloproteinase inhibitor GM6001. These results suggest that the tetraspanin CD9 modulates the ADAM17-mediated shedding of LR11 in various leukemia cell lines and that the association between LR11 and CD9 on the cell surface has an important role in the ADAM17-mediated shedding mechanism.
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影响因子：
4.4
作者：
Arduise, Cecile;Abache, Toufik;Le Naour, Francoise
通讯作者：
Le Naour, Francoise
DOI：
10.1161/atvbaha.106.137091
发表时间：
2007-05-01
影响因子：
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Jiang, Meizi;Bujo, Hideaki;Saito, Yasushi
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