Regulation of Blos1 by IRE1 prevents the accumulation of Huntingtin protein aggregates

Huntingtons Disease is characterized by accumulation of the aggregation-prone mutant Huntingtin (mHTT) protein. Here, we show that expression 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 accumulation of larger mHTT aggregates and increased cell death. Although mHTT is degraded by macroautophagy when highly expressed, we show that prior to the formation of large aggregates, mHTT is degraded via an ESCRT-dependent, endosomal microautophagy pathway. This pathway is enhanced by Blos1 degradation and appears to protect cells from a toxic, less aggregated form of mHTT. Condensed titleBlos1 regulation protects from Huntingtin protein aggregation