Canuel Maryssa, Libin Yuan, Morales Carlos R
Department of Anatomy and Cell Biology, McGill University, 3640 University Street, Montreal, Quebec, Canada.
Histol Histopathol. 2009 Apr;24(4):481-92. doi: 10.14670/HH-24.481.
The delivery of soluble lysosomal proteins to the lysosomes is dependent primarily on the mannose 6-phosphate receptor (MPR). The MPR has been demonstrated to attain the early endosomes via a process that requires the interaction of its cytosolic domain with the GGA and AP-1 adaptor proteins. Additionally, the MPR can be recycled back to the trans-Golgi network (TGN) through its interaction with the retromer complex. Interestingly, in I-cell disease (ICD), in which the MPR pathway is non-functional, many soluble lysosomal proteins continue to traffic to the lysosomes. This observation led to the discovery that sortilin is responsible for the MPR-independent targeting of the sphingolipid activator proteins (SAPs) and acid sphingomyelinase (ASM). More recently, our laboratory has tested the hypothesis that sortilin is also capable of sorting a variety of cathepsins that exhibit varying degrees of MPR-independent transport. We have demonstrated that the transport of cathepsin D is partially dependent upon sortilin, that cathepsin H requires sortilin, and that cathepsins K and L attain the lysosomes in a sortilin-independent fashion. As a type-1 receptor, sortilin also has numerous cytosolic binding partners. It has been observed that like the MPR, the anterograde trafficking of sortilin and its cargo require both GGAs and AP-1. Similarly, the retrograde recycling pathway of sortilin also involves an interaction with retromer through a YXXphi site in the cytosolic tail of sortilin. In conclusion, the cytosolic domains of sortilin and MPR possess a high degree of functional homology and both receptors share a conserved trafficking mechanism.
可溶性溶酶体蛋白向溶酶体的转运主要依赖于甘露糖6-磷酸受体（MPR）。已证明MPR通过其胞质结构域与GGA和AP-1衔接蛋白相互作用的过程进入早期内体。此外，MPR可通过与回收蛋白复合物相互作用循环回到反式高尔基体网络（TGN）。有趣的是，在MPR途径无功能的I型细胞病（ICD）中，许多可溶性溶酶体蛋白仍继续转运至溶酶体。这一观察结果导致发现分拣蛋白负责鞘脂激活蛋白（SAPs）和酸性鞘磷脂酶（ASM）的不依赖MPR的靶向运输。最近，我们实验室测试了分拣蛋白也能够分拣多种表现出不同程度不依赖MPR运输的组织蛋白酶的假说。我们已经证明组织蛋白酶D的转运部分依赖于分拣蛋白，组织蛋白酶H需要分拣蛋白，而组织蛋白酶K和L以不依赖分拣蛋白的方式进入溶酶体。作为一种1型受体，分拣蛋白也有许多胞质结合伴侣。已观察到，与MPR一样，分拣蛋白及其货物的顺向运输需要GGA和AP-1。同样，分拣蛋白的逆行回收途径也涉及通过分拣蛋白胞质尾部的YXXphi位点与回收蛋白相互作用。总之，分拣蛋白和MPR的胞质结构域具有高度的功能同源性，并且这两种受体共享保守的运输机制。
