Escudero Claudia A, Lazo Oscal M, Galleguillos Carolina, Parraguez Jose I, Lopez-Verrilli Maria A, Cabeza Carolina, Leon Luisa, Saeed Uzma, Retamal Claudio, Gonzalez Alfonso, Marzolo Maria-Paz, Carter Bruce D, Court Felipe A, Bronfman Francisca C
Faculty of Biological Sciences, Physiology Department, Pontificia Universidad Católica, Santiago, CP 8331010, Chile.
J Cell Sci. 2014 May 1;127(Pt 9):1966-79. doi: 10.1242/jcs.141754. Epub 2014 Feb 25.
The p75 neurotrophin receptor (p75, also known as NGFR) is a multifaceted signalling receptor that regulates neuronal physiology, including neurite outgrowth, and survival and death decisions. A key cellular aspect regulating neurotrophin signalling is the intracellular trafficking of their receptors; however, the post-endocytic trafficking of p75 is poorly defined. We used sympathetic neurons and rat PC12 cells to study the mechanism of internalisation and post-endocytic trafficking of p75. We found that p75 internalisation depended on the clathrin adaptor protein AP2 and on dynamin. More surprisingly, p75 evaded the lysosomal route at the level of the early endosome, instead accumulating in two different types of endosomes, Rab11-positive endosomes and multivesicular bodies (MVBs) positive for CD63, a marker of the exosomal pathway. Consistently, depolarisation by KCl induced the liberation of previously endocytosed full-length p75 into the extracellular medium in exosomes. Thus, p75 defines a subpopulation of MVBs that does not mature to lysosomes and is available for exosomal release by neuronal cells.
p75神经营养因子受体（p75，也称为NGFR）是一种多面性的信号受体，可调节神经元生理功能，包括神经突生长以及存活和死亡决定。调节神经营养因子信号传导的一个关键细胞方面是其受体的细胞内运输；然而，p75的内吞后运输情况却知之甚少。我们利用交感神经元和大鼠嗜铬细胞瘤（PC12）细胞来研究p75的内化机制和内吞后运输。我们发现p75的内化依赖于网格蛋白衔接蛋白AP2和发动蛋白。更令人惊讶的是，p75在早期内体水平避开了溶酶体途径，而是积聚在两种不同类型的内体中，即Rab11阳性内体和对CD63呈阳性的多囊泡体（MVB），CD63是外泌体途径的标志物。一致的是，氯化钾诱导的去极化导致先前内吞的全长p75以外泌体的形式释放到细胞外培养基中。因此，p75定义了一类不会成熟为溶酶体的MVB亚群，可用于神经元细胞的外泌体释放。
