Retromer as a critical regulator of endosome maturation?

逆转录酶是内体成熟的关键调节因子？

• 批准号: 245888543
• 负责人: Dr. Florian Steinberg
• 金额: --
• 依托单位: Zentrum für Biosystemanalyse
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/245888543?language=en
• 关键词: Retromer; critical; regulator; endosome; maturation

Retromer is an evolutioanry conserved multi-protein complex which recycles internalized integral membrane proteins from endosomes back to the plasma membrane or back to the trans golgi network. Mutations in retromer cause hereditary Parkinson's disease which makes a thorough mechanistic understanding of this complex necessary. We have recently identified a major new function for this complex in the control of the late endosomal/lysosomal small GTPases protein RAB7. In the absence of retromer or the retromer bound protein TBC1D5, RAB7 is no longer controlled in its activity state, which leads to gross hyperactivation and endo-lysosomal accumulation of this small GTPase. This hyperactivation causes defects in the RAB7 dependent autophagy of mitochondria. However, given the many functions of this small GTPase, the defects in mitophagy cannot be the only effect of deregulated RAB7. In this context, we have substantial preliminary data showing that the RAB7 mediated maturation of early into late endosomes is strikingly altered in the absence of retromer. This in turn leads to a range of observed trafficking defects, among them the aberrant sorting of lysosomal hydrolases, which are not delivered to lysosomes but instead secreted into the extracellular space. This proposal seeks to investigate the precise mechanistic basis of the observed defects to really begin to understand the novel function of retromer in the control of RAB7 activity. The knowledge gained here may well prove to be valuable for our understanding of retromer's role in Parkinson's disease.

Retromer是一种进化上保守的多蛋白复合物，它能将内化的膜蛋白从内体重新带回质膜或高尔基体网络。retromer突变导致遗传性帕金森病，这使得彻底的机制理解这一复杂的必要。我们最近已经确定了一个主要的新功能，这个复杂的控制晚期内体/溶酶体小GTPases蛋白RAB 7。在不存在逆转录酶或逆转录酶结合蛋白TBC 1D 5的情况下，RAB 7不再被控制在其活性状态，这导致该小GT3的总体超活化和内-溶酶体积累。这种超活化导致线粒体的RAB 7依赖性自噬的缺陷。然而，考虑到这种小GT3的许多功能，线粒体自噬中的缺陷不可能是RAB 7失调的唯一影响。在这种情况下，我们有大量的初步数据表明，RAB 7介导的成熟的早期到晚期内体是惊人的改变，在没有逆转录酶。这又导致一系列观察到的运输缺陷，其中包括溶酶体水解酶的异常分选，其不被递送到溶酶体，而是分泌到细胞外空间。该建议旨在研究所观察到的缺陷的精确机制基础，以真正开始理解逆转录酶在控制RAB 7活性中的新功能。在这里获得的知识可能会被证明是有价值的，我们了解retromer在帕金森病中的作用。