A unique lysophospholipid acyltransferase (LPAT) antagonist, CI-976, affects secretory and endocytic membrane trafficking pathways
A unique lysophospholipid acyltransferase (LPAT) antagonist, CI-976, affects secretory and endocytic membrane trafficking pathways
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DOI：
10.1242/jcs.02435
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发表时间：
2005-07-15
影响因子：
4
通讯作者：
Brown, WJ
中科院分区：
文献类型：
--
作者：
Chambers, K;Judson, B;Brown, WJ
先前的研究已经表明，药物CI-976抑制高尔基体复合体相关的溶血磷脂酰基转移酶（LPAT）活性刺激高尔基体小管形成和随后的驻留高尔基体蛋白重新分布到内质网（ER）。在这里，我们表明，CI-976刺激从高尔基复合体的所有亚室的小管形成，并且这些小管通常独立地形成，即单个小管通常不包含来自不同亚室的标记物。而顺式，内侧和反式高尔基体膜重新分配到ER，反式高尔基体网络（TGN）崩溃回一个紧凑的adrenuclear的位置类似于所看到的布雷菲德菌素A（BFA）治疗。同样类似于BFA，CI-976诱导内体小管的形成，但与BFA不同，这些小管不与TGN小管融合。最后，CI-976产生了一个明显的不可逆的块在转铁蛋白（Tf）和转铁蛋白受体（TfRs）的内吞再循环途径，但没有直接影响从细胞表面的Tf摄取。Tf和TfRs在位于中央的Rab 11阳性囊泡中积累，表明CI-976抑制了从中央内吞再循环区室输出货物。这些结果，与以前的研究一起，表明CI-976抑制多个膜运输步骤，包括内吞和分泌途径中发现的步骤，并意味着溶血磷脂酰基转移酶在膜运输中的作用更广泛。
Previous studies have shown that inhibition of a Golgi-complex-associated lysophospholipid acyltransferase (LPAT) activity by the drug CI-976 stimulates Golgi tubule formation and subsequent redistribution of resident Golgi proteins to the endoplasmic reticulum (ER). Here, we show that CI-976 stimulates tubule formation from all subcompartments of the Golgi complex, and often these tubules formed independently, i.e. individual tubules usually did not contain markers from different subcompartments. Whereas the cis, medial and trans Golgi membranes redistributed to the ER, the trans Golgi network (TGN) collapsed back to a compact juxtanuclear position similar to that seen with brefeldin A (BFA) treatment. Also similar to BFA, CI-976 induced the formation of endosome tubules, but unlike BFA, these tubules did not fuse with TGN tubules. Finally, CI-976 produced an apparently irreversible block in the endocytic recycling pathway of transferrin (Tf) and Tf receptors (TfRs) but had no direct effect on Tf uptake from the cell surface. Tf and TfRs accumulated in centrally located, Rab11-positive vesicles indicating that CI-976 inhibits export of cargo from the central endocytic recycling compartment. These results, together with previous studies, demonstrate that CI-976 inhibits multiple membrane trafficking steps, including ones found in the endocytic and secretory pathways, and imply a wider role for lysophospholipid acyltransferases in membrane trafficking.