Retromer as a critical regulator of endosome maturation?

反转录体是一种进化保守的多蛋白复合物，它将内化的完整膜蛋白从核内体再循环回质膜或反式高尔基网络。逆转录酶的突变导致遗传性帕金森病，这使得对该复合体的彻底的机制理解是必要的。我们最近发现了该复合体在控制晚期内体/溶酶体小GTPases蛋白RAB7方面的主要新功能。在缺乏反转录酶或反转录酶结合蛋白TBC1D5的情况下，RAB7不再处于其活性状态，从而导致这种小GTPase的过度激活和内溶酶体积累。这种过度激活导致线粒体依赖RAB7的自噬缺陷。然而，考虑到这个小GTPase的许多功能，线粒体自噬缺陷不可能是RAB7不受调控的唯一影响。在这种情况下，我们有大量的初步数据表明，RAB7介导的早期到晚期内体的成熟在缺乏逆转录酶的情况下发生了显著改变。这反过来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，这些酶不是传递给溶酶体，而是分泌到细胞外空间。该建议旨在调查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RAB7活性中的新功能。在这里获得的知识很可能证明对我们理解逆转录酶在帕金森病中的作用是有价值的。

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.