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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A trans-Golgi network golgin is required for the regulated secretion of TNF in activated macrophages in vivo
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A trans-Golgi network golgin is required for the regulated secretion of TNF in activated macrophages in vivo

机译：在体内激活的巨噬细胞中TNF的调节分泌需要反式高尔基网络古尔金

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The transmembrane precursor of tumor necrosis factor-α (TNF) exits the trans-Golgi network (TGN) in tubular carriers for subsequent trafficking and delivery to the cell surface; however, the molecular machinery responsible for Golgi export is unknown. We previously reported that members of the TGN golgin family are associated with subdomains and tubules of the TGN. Here, we show that the TGN golgin, p230/golgin-245 (p230), is essential for intracellular trafficking and cell surface delivery of TNF in trans-fected HeLa cells and activated macrophages. Live-cell imaging revealed that TNF transport from the TGN is mediated selectively by tubules and carriers marked by p230. Significantly, LPS activation of macrophages resulted in a dramatic increase of p230-labeled tubules and carriers emerging from the TGN, indicating that macrophages up-regulate the transport pathway for TNF export. Depletion of p230 in LPS-stimulated macrophages reduced cell surface delivery of TNF by > 10-fold compared with control cells. To determine whether p230 depletion blocked TNF secretion in vivo, we generated retrogenic mice expressing a microRNA-vector to silence p230. Bone-marrow stem cells were transduced with recombinant retrovirus containing microRNA constructs and transplanted into irradiated recipients. LPS-activated peritoneal macrophages from p230 miRNA retrogenic mice were depleted of p230 and had dramatically reduced levels of cell surface TNF. Overall, these studies have identified p230 as a key regulator of TNF secretion and have shown that LPS activation of macrophages results in increased Golgi carriers for export. Also, we have demonstrated a previously undescribed approach to control cytokine secretion by the specific silencing of trafficking machinery.
机译：肿瘤坏死因子-α（TNF）的跨膜前体在肾小管载体中离开反式高尔基网络（TGN），以随后的运输和传递至细胞表面。但是，负责高尔基体出口的分子机制尚不清楚。先前我们曾报道TGN golgin家族的成员与TGN的亚域和肾小管相关。在这里，我们显示TGN戈尔金，p230 / golgin-245（p230），对于转染HeLa细胞和活化的巨噬细胞中TNF的细胞内运输和细胞表面传递至关重要。活细胞成像显示，来自TGN的TNF转运是由以p230标记的小管和载体选择性介导的。重要的是，巨噬细胞的LPS活化导致从TGN出现的p230标记的小管和载体急剧增加，表明巨噬细胞上调了TNF出口的转运途径。与对照细胞相比，LPS刺激的巨噬细胞中p230的消耗使TNF的细胞表面传递减少了10倍以上。为了确定p230耗竭是否在体内阻断了TNF的分泌，我们生成了表达microRNA载体使p230沉默的逆转录小鼠。用含有microRNA构建体的重组逆转录病毒转导骨髓干细胞，并将其移植到受辐照的受体中。来自p230 miRNA逆转录小鼠的LPS激活的腹膜巨噬细胞中的p230耗尽，并且细胞表面TNF的水平大大降低。总体而言，这些研究已将p230确定为TNF分泌的关键调节剂，并表明巨噬细胞的LPS活化导致出口的高尔基体携带者增多。而且，我们已经证明了以前未描述的通过贩运机制的特异性沉默来控制细胞因子分泌的方法。

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