The HSP90 inhibitor geldanamycin perturbs endosomal structure and drives recycling ErbB2 and transferrin to modified MVBs/lysosomal compartments
The HSP90 inhibitor geldanamycin perturbs endosomal structure and drives recycling ErbB2 and transferrin to modified MVBs/lysosomal compartments
复制标题
DOI：
10.1091/mbc.e12-04-0282
复制
发表时间：
2013-01-15
影响因子：
3.3
通讯作者：
Tacchetti, Carlo
中科院分区：
文献类型：
--
作者：
Cortese, Katia;Howes, Mark T.;Tacchetti, Carlo
ErbB2受体是临床验证的癌症靶点，其内化和转运机制仍然知之甚少。热休克蛋白90抑制剂，如格尔达霉素（GA），已被开发用于靶向受体降解或调节下游信号传导。尽管有大量的研究，ErbB2在GA刺激下的进入途径和胞后分选仍然存在争议。我们报道ErbB2水平负向影响网格蛋白介导的细胞内吞（CME）能力。事实上，高水平的受体是其自身低内化率的原因。GA处理不直接调节ErbB2 CME率，但它影响ErbB2的循环命运，通过扰乱早期/循环内体结构和分选能力，将受体定向到修饰的多泡内体（MVBs）和溶酶体室。这种活性的发生与货物与HSP90的相互作用无关，因为ErbB2和组成性回收的、不依赖于HSP90的转铁蛋白受体都存在于修饰的核内体和异常的、细长的回收小管中，从而导致修饰的MVBs/溶酶体。我们认为，GA作为其抗癌活性的一部分，干扰了早期/再循环核内体的分类，将再循环的货物导向混合核内体区室。
The ErbB2 receptor is a clinically validated cancer target whose internalization and trafficking mechanisms remain poorly understood. HSP90 inhibitors, such as geldanamycin (GA), have been developed to target the receptor to degradation or to modulate downstream signaling. Despite intense investigations, the entry route and postendocytic sorting of ErbB2 upon GA stimulation have remained controversial. We report that ErbB2 levels inversely impact cell clathrin-mediated endocytosis (CME) capacity. Indeed, the high levels of the receptor are responsible for its own low internalization rate. GA treatment does not directly modulate ErbB2 CME rate but it affects ErbB2 recycling fate, routing the receptor to modified multivesicular endosomes (MVBs) and lysosomal compartments, by perturbing early/recycling endosome structure and sorting capacity. This activity occurs irrespective of the cargo interaction with HSP90, as both ErbB2 and the constitutively recycled, HSP90-independent, transferrin receptor are found within modified endosomes, and within aberrant, elongated recycling tubules, leading to modified MVBs/lysosomes. We propose that GA, as part of its anticancer activity, perturbs early/recycling endosome sorting, routing recycling cargoes toward mixed endosomal compartments.