FOXO1 controls protein synthesis and transcript abundance of mutant polyglutamine proteins, preventing protein aggregation

Gabriel Vasata Furtado, Jing Yang, Di Wu, Christos I Papagiannopoulos, Hanna M Terpstra, E F Elsiena Kuiper, Sybille Krauss, Wei-Guo Zhu, Harm H Kampinga, Steven Bergink*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

FOXO1, a transcription factor downstream of the insulin/insulin like growth factor axis has been linked to protein degradation. Elevated expression of FOXO orthologs can also prevent aggregation of CAG-repeat disease causing polyglutamine (polyQ) proteins but whether FOXO1 targets mutant proteins for degradation is unclear. Here we show that increased expression of FOXO1 prevents toxic polyQ aggregation in human cells while reducing FOXO1 levels has the opposite effect and accelerates it. Although FOXO1 indeed stimulates autophagy, its effect on polyQ aggregation is independent of autophagy, UPS mediated protein degradation and is not due to a change in mutant polyQ protein turnover. Instead FOXO1 specifically downregulates protein synthesis rates from expanded pathogenic CAG repeat transcripts. FOXO1 orchestrates a change in the composition of proteins that occupy mutant expanded CAG transcripts, including the recruitment of IGF2BP3. This mRNA binding protein enables a FOXO1 driven decrease in pathogenic expanded CAG transcript- and protein levels, thereby reducing the initiation of amyloidogenesis. Our data thus demonstrate that FOXO1 not only preserves protein homeostasis at multiple levels, but also reduces accumulation of aberrant RNA species that may co-contribute to the toxicity in CAG-repeat diseases.

Original languageEnglish
JournalHuman Molecular Genetics
DOIs
Publication statusE-pub ahead of print - 2-Apr-2021

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