Cambridge Institute for Medical Research and Department of Clinical Biochemistry, University of Cambridge, Cambridge CB2 0XY, UK.
Biochem Soc Trans. 2010 Dec;38(6):1413-6. doi: 10.1042/BST0381413.
The delivery of endocytosed cargo to lysosomes occurs through kissing and direct fusion of late endosomes/MVBs (multivesicular bodies) and lysosomes. Live-cell and electron microscopy experiments together with cell-free assays have allowed us to describe the characteristics of the delivery process and determine the core protein machinery required for fusion. The ESCRT (endosomal sorting complex required for transport) machinery is required for MVB biogenesis. The HOPS (homotypic fusion and vacuole protein sorting) complex is required for endosome-lysosome tethering and a trans-SNARE (soluble N-ethylmaleimide-sensitive factor-attachment protein receptor) complex including the R-SNARE VAMP7 (vesicle-associated membrane protein 7) mediates endosome-lysosome membrane fusion. Protein-binding partners of VAMP7 including the clathrin adaptors AP-3 (adaptor protein 3) and Hrb (HIV Rev-binding protein) are required for its correct intracellular localization and function. Overall, co-ordination of the activities of ESCRT, HOPS and SNARE complexes are required for efficient delivery of endocytosed macromolecules to lysosomes. Endosome-lysosome fusion results in a hybrid organelle from which lysosomes are re-formed. Defects in fusion and/or lysosome reformation occur in a number of lysosome storage diseases.
内吞 cargo 递送至溶酶体是通过晚期内体/MVB（多泡体）与溶酶体的“亲吻”和直接融合来实现的。活细胞和电子显微镜实验以及无细胞测定共同揭示了该递呈过程的特征，并确定了融合所必需的核心蛋白机制。内体分选复合物必需运输（ESCRT）机制对于 MVB 的生物发生是必需的。同源融合和液泡蛋白分选（HOPS）复合物对于内体-溶酶体的 tethering 是必需的，并且包括 R-SNARE VAMP7（囊泡相关膜蛋白 7）在内的跨 SNARE（可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体）复合物介导了内体-溶酶体的膜融合。VAMP7 的蛋白结合伴侣，包括网格蛋白衔接蛋白 AP-3（衔接蛋白 3）和 HIV Rev 结合蛋白（Hrb），对于其正确的细胞内定位和功能是必需的。总的来说，ESCRT、HOPS 和 SNARE 复合物的活性协调对于内吞大分子向溶酶体的有效递呈是必需的。内体-溶酶体融合导致从其中重新形成溶酶体的杂交细胞器。在许多溶酶体贮积病中，融合和/或溶酶体再形成缺陷发生。
