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

Abstract

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 excessive accumulation of mHTT aggregates in both cultured cells and primary neurons. 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, 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. Condensed titleBlos1 regulation protects from Huntingtin aggregation Short summaryHere the authors demonstrate that the regulation of Blos1 by the unfolded protein response prevents the excessive accumulation of Huntingtin, the protein that underlies Huntingtons disease. This pathway involves the macroautophagy-independent degradation of Huntingtin prior to its forming large aggregates.