Role of the ribosomal quality control machinery in nucleocytoplasmic translocation of polyQ-expanded huntingtin exon-1

• DOI: 10.1016/j.bbrc.2017.08.126
• Publication Date: 2017-08-31T10:02:50Z
• Authors: Ju Zheng; Junsheng Yang; Young-Jun Choe; Xinxin Hao; Xiuling Cao; Qian Zhao; Yuejie Zhang; Vanessa Franssens; F. Ulrich Hartl; Thomas Nyström; Joris Winderickx; Beidong Liu
• Keywords: Cell Nucleus; 0301 basic medicine; Huntingtin Protein; Nucleocytoplasmic Transport Proteins; 03 medical and health sciences; Active Transport, Cell Nucleus; Humans; Exons; Peptides; Ribosomes; Protein Binding

The subcellular localization of polyQ-expanded huntingtin exon1 (Httex1) modulates polyQ toxicity in models of Huntington's disease. Using genome-wide screens in a yeast model system, we report that the ribosome quality control (RQC) machinery, recently implicated in neurodegeneration, is a key determinant for the nucleocytoplasmic distribution of Httex1-103Q. Deletion of the RQC genes, LTN1 or RQC1, caused the accumulation of Httex1-103Q in the nucleus through a process that required the CAT-tail tagging activity of Rqc2 and transport via the nuclear pore complex. We provide evidence that nuclear accumulation of Httex1-103Q enhances its cytotoxicity, suggesting that the RQC machinery plays an important role in protecting cells against the adverse effects of polyQ expansion proteins.