Department of Cell Biology, University of Virginia, Charlottesville, VA
Department of Cell Biology, University of Virginia, Charlottesville, VA.
J Cell Biol. 2018 Sep 3;217(9):3141-3159. doi: 10.1083/jcb.201711039. Epub 2018 Jun 15.
Neurons are large and long lived, creating high needs for regulating protein turnover. Disturbances in proteostasis lead to aggregates and cellular stress. We characterized the behavior of the short-lived dendritic membrane proteins Nsg1 and Nsg2 to determine whether these proteins are degraded locally in dendrites or centrally in the soma. We discovered a spatial heterogeneity of endolysosomal compartments in dendrites. Early EEA1-positive and late Rab7-positive endosomes are found throughout dendrites, whereas the density of degradative LAMP1- and cathepsin (Cat) B/D-positive lysosomes decreases steeply past the proximal segment. Unlike in fibroblasts, we found that the majority of dendritic Rab7 late endosomes (LEs) do not contain LAMP1 and that a large proportion of LAMP1 compartments do not contain CatB/D. Second, Rab7 activity is required to mobilize distal predegradative LEs for transport to the soma and terminal degradation. We conclude that the majority of dendritic LAMP1 endosomes are not degradative lysosomes and that terminal degradation of dendritic cargos such as Nsg1, Nsg2, and DNER requires Rab7-dependent transport in LEs to somatic lysosomes.
神经元体积大且寿命长，因此对调节蛋白质周转率的要求很高。蛋白质平衡的破坏会导致聚集和细胞应激。我们对寿命较短的树突膜蛋白 Nsg1 和 Nsg2 的行为进行了表征，以确定这些蛋白质是在树突中局部降解，还是在胞体中集中降解。我们发现树突内的内体小泡具有空间异质性。早期 EEA1 阳性和晚期 Rab7 阳性的内体在整个树突中都有发现，而降解性 LAMP1 和组织蛋白酶（Cat）B/D 阳性溶酶体的密度在近端段之后急剧下降。与成纤维细胞不同，我们发现大多数树突 Rab7 晚期内体（LE）不含有 LAMP1，并且很大一部分 LAMP1 区室不含有 CatB/D。其次，Rab7 活性对于将远端预降解的 LE 动员到胞体并进行终末降解是必需的。我们得出结论，大多数树突 LAMP1 内体不是降解性溶酶体，并且 Nsg1、Nsg2 和 DNER 等树突货物的终末降解需要 Rab7 依赖性运输到体性溶酶体。
