Regulation of Blos1 by IRE1 prevents the accumulation of Huntingtin protein aggregates.
Regulation of Blos1 by IRE1 prevents the accumulation of Huntingtin protein aggregates.
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DOI：
10.1091/mbc.e22-07-0281
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发表时间：
2022-11-01
影响因子：
3.3
通讯作者：
Hollien, Julie
中科院分区：
文献类型：
--
作者：
Bae, Donghwi;Jones, Rachel Elizabeth;Piscopo, Katherine M.;Tyagi, Mitali;Shepherd, Jason D.;Hollien, Julie
亨廷顿病的特点是容易聚集的突变亨廷顿蛋白 (mHTT) 蛋白的积累。在这里，我们发现小鼠培养细胞中 mHTT 外显子 1 的表达会激活内质网应激的跨膜传感器 IRE1，导致 Blos1 mRNA 降解以及溶酶体和晚期内体向微管组织中心重新定位。过度的 Blos1 降解会导致培养细胞和原代神经元中 mHTT 聚集物过度积累。尽管mHTT在高表达时会被巨自噬降解，但我们发现，在形成大聚集体之前，mHTT是通过与内体微自噬一致的ESCRT依赖性、不依赖巨自噬的途径降解的。该途径通过 Blos1 降解得到增强，并且似乎可以保护细胞免受有毒、聚集程度较低的 mHTT 的侵害。
Huntington’s disease is characterized by accumulation of the aggregation-prone mutant Huntingtin (mHTT) protein. Here, we show that expression of exon 1 of mHTT in mouse cultured cells activates IRE1, the transmembrane sensor of stress in the endoplasmic reticulum, leading to degradation of the Blos1 mRNA and repositioning of lysosomes and late endosomes toward the microtubule organizing center. Overriding Blos1 degradation results in excessive accumulation of mHTT aggregates in both cultured cells and primary neurons. Although mHTT is degraded by macroautophagy when highly expressed, we show that before the formation of large aggregates, mHTT is degraded via an ESCRT-dependent, macroautophagy-independent pathway consistent with endosomal microautophagy. This pathway is enhanced by Blos1 degradation and appears to protect cells from a toxic, less aggregated form of mHTT.