Negative regulation of phosphatidylinositol 3-phosphate levels in early-to-late endosome conversion.
Negative regulation of phosphatidylinositol 3-phosphate levels in early-to-late endosome conversion.
复制标题
早期到晚期内体转化中磷脂酰肌醇 3-磷酸水平的负调节
DOI：
10.1083/jcb.201506081
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发表时间：
2016-01-18
期刊：
影响因子：
--
通讯作者：
Yang C
中科院分区：
文献类型：
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作者：
Liu K;Jian Y;Sun X;Yang C;Gao Z;Zhang Z;Liu X;Li Y;Xu J;Jing Y;Mitani S;He S;Yang C
C.线虫SORF-1和SORF-2及其哺乳动物同系物WDR 91和WDR 81通过与PI 3 K复合物的Beclin 1亚基形成复合物，在早期至晚期内体转化中维持适当的PtdIns 3 P水平。磷脂酰肌醇3-磷酸（PtdIns 3 P）在内体融合、再循环、分选和早期至晚期内体转化中起核心作用，但是确定如何实现正确的内体PtdIns 3 P水平的机制在很大程度上仍然是难以捉摸的。在这里，我们确定了两个新的因素，SORF-1和SORF-2，作为必不可少的PtdIns 3 P调节器在秀丽隐杆线虫。sorf-1或sorf-2的缺失导致内体PtdIns 3 P大大升高，这驱动早期内体的过度融合。sorf-1和sorf-2与Rab转换基因协同作用以抑制PtdIns 3 P的合成，允许其周转用于内体转化。SORF-1和SORF-2与BEC-1/Beclin 1形成复合物，它们的缺失导致磷脂酰肌醇3-激酶（PI 3 K）复合物活性升高。在哺乳动物细胞中，SORF-1和SORF-2的同源物WDR 91和WDR 81的失活诱导Beclin 1依赖性的PtdIns 3 P富集的内体的扩大和表皮生长因子受体的缺陷性降解。WDR 91和WDR 81与Beclin 1相互作用并抑制PI 3 K复合物活性。这些发现揭示了一个保守的机制，控制适当的PtdIns 3 P水平在早期到晚期的内体转换。
C. elegans SORF-1 and SORF-2 and their mammalian homologs WDR91 and WDR81 maintain appropriate PtdIns3P levels in early-to-late endosome conversion by forming a complex with the Beclin1 subunit of the PI3K complex. Phosphatidylinositol 3-phosphate (PtdIns3P) plays a central role in endosome fusion, recycling, sorting, and early-to-late endosome conversion, but the mechanisms that determine how the correct endosomal PtdIns3P level is achieved remain largely elusive. Here we identify two new factors, SORF-1 and SORF-2, as essential PtdIns3P regulators in Caenorhabditis elegans. Loss of sorf-1 or sorf-2 leads to greatly elevated endosomal PtdIns3P, which drives excessive fusion of early endosomes. sorf-1 and sorf-2 function coordinately with Rab switching genes to inhibit synthesis of PtdIns3P, allowing its turnover for endosome conversion. SORF-1 and SORF-2 act in a complex with BEC-1/Beclin1, and their loss causes elevated activity of the phosphatidylinositol 3-kinase (PI3K) complex. In mammalian cells, inactivation of WDR91 and WDR81, the homologs of SORF-1 and SORF-2, induces Beclin1-dependent enlargement of PtdIns3P-enriched endosomes and defective degradation of epidermal growth factor receptor. WDR91 and WDR81 interact with Beclin1 and inhibit PI3K complex activity. These findings reveal a conserved mechanism that controls appropriate PtdIns3P levels in early-to-late endosome conversion.