Elimination of virus- like particles reduces protein aggregation and extends replicative lifespan in Saccharomyces cerevisiae

• 成果类型: Article
• 署名作者: Schneider, K. L.; Hao, X.; Keuenhof, K. S.; Berglund, L. L.; Fischbach, A.; Ahmadpour, D.; Chawla, S.; Gomez, P.; Hoog, J. L.; Widlund, P. O.; Nystrom, T.
• 署名单位: Cochlear; Max Planck Society; Sahlgrenska University Hospital; Chalmers University of Technology; Pompeu Fabra University; University of Gothenburg; University of Gothenburg
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12129
• DOI: 10.1073/pnas.2313538121
• 发表日期: 2024-03-25
• 关键词: asymmetric inheritance; transposable elements; misfolded proteins; damaged proteins; endogenous retroviruses; reverse-transcriptase; ty1 element; p-bodies; yeast; transposition

摘要

A major consequence of aging and stress, in yeast to humans, is an increased accumulation of protein aggregates at distinct sites within the cells. Using genetic screens, immunoelectron microscopy, and three- dimensional modeling in our efforts to elucidate the importance of aggregate annexation, we found that most aggregates in yeast accumulate near the surface of mitochondria. Further, we show that virus - like particles (VLPs), which are part of the retrotransposition cycle of Ty elements, are markedly enriched in these sites of protein aggregation. RNA interference- mediated silencing of Ty expression perturbed aggregate sequestration to mitochondria, reduced overall protein aggregation, mitigated toxicity of a Huntington's disease model, and expanded the replicative lifespan of yeast in a partially Hsp104- dependent manner. The results are in line with recent data demonstrating that VLPs might act as aging factors in mammals, including humans, and extend these findings by linking VLPs to a toxic accumulation of protein aggregates and raising the possibility that they might negatively influence neurological disease progression.