Harvard Medical School, Boston, MA.
Harvard Medical School, Boston, MA
J Cell Biol. 2018 May 7;217(5):1757-1776. doi: 10.1083/jcb.201708168. Epub 2018 Mar 13.
Proteasome inhibitors are used as research tools and to treat multiple myeloma, and proteasome activity is diminished in several neurodegenerative diseases. We therefore studied how cells compensate for proteasome inhibition. In 4 h, proteasome inhibitor treatment caused dramatic and selective induction of (but not other autophagy genes) and , which binds ubiquitinated proteins and GABARAPL1 on autophagosomes. Knockdown of or reduced cell survival upon proteasome inhibition. induction requires the transcription factor nuclear factor (erythroid-derived 2)-like 1 (Nrf1), which simultaneously induces proteasome genes. After 20-h exposure to proteasome inhibitors, cells activated autophagy and expression of most autophagy genes by an Nrf1-independent mechanism. Although p62 facilitates the association of ubiquitinated proteins with autophagosomes, its knockdown in neuroblastoma cells blocked the buildup of ubiquitin conjugates in perinuclear aggresomes and of sumoylated proteins in nuclear inclusions but did not reduce the degradation of ubiquitinated proteins. Thus, upon proteasome inhibition, cells rapidly induce expression, which enhances survival primarily by sequestering ubiquitinated proteins in inclusions.
蛋白酶体抑制剂被用作研究工具和治疗多发性骨髓瘤的药物，并且在几种神经退行性疾病中蛋白酶体的活性降低。因此，我们研究了细胞如何补偿蛋白酶体抑制。在 4 小时内，蛋白酶体抑制剂处理导致 （但不是其他自噬基因）和 的显著和选择性诱导，后者结合泛素化蛋白和自噬体上的 GABARAPL1。 或 的敲低可降低蛋白酶体抑制后的细胞存活率。 诱导需要转录因子核因子（红系衍生 2 样 1）（Nrf1），其同时诱导蛋白酶体基因。在暴露于蛋白酶体抑制剂 20 小时后，细胞通过 Nrf1 独立的机制激活自噬和大多数自噬基因的表达。虽然 p62 促进了泛素化蛋白与自噬体的结合，但在神经母细胞瘤细胞中敲低 p62 不会减少泛素化蛋白的降解，但会阻止核周聚集物中泛素缀合物的积累和核内包涵体中 sumoylated 蛋白的积累。因此，在蛋白酶体抑制后，细胞迅速诱导 表达，其主要通过将泛素化蛋白隔离在包涵体中来增强存活。
