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

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.

In vivo suppression of polyglutamine aggregation via co-condensation of the molecular chaperone DNAJB6

“…Using ATG5 -/- mouse embryonic fibroblasts, we have previously shown that protein degradation via (macro)autophagy was also not required for DNAJB6b-mediated suppression of polyQ aggregation 25 . To extend these data to the hippomorphic DNAJB6b variants, we employed here a complementary approach that did not rely on knockout cell lines, but on chemical blockage of the autophagic machinery with a cocktail of three lysosome-targeting drugs (bafilomycin A, pepstatin A, and E64d) 40 . In line with results published earlier 25 , we confirmed that cells do not exploit the (macro)autophagy-lysosome pathway to process DNAJB6b-chaperoned polyQ assemblies ( Figures S5G-K ).…”

What’s Diet Got to Do With It? Basic and Clinical Science Behind Diet and Acne

“…38 Interestingly, genetic polymorphisms of the AR have been shown to cause variable affinity of FOXO1 for the AR; specifically, shorter CAG (cytosine, adenine, guanine) repeat length may lead to decreased FOXO1 binding and is associated with an increased risk for acne. [41][42][43] In addition to its effects on the hair follicle, IGF-1 stimulates production of testosterone and dehydroepiandrosterone as well as activates 5α-reductase, leading to higher dihydrotestosterone levels, which activate the AR with higher affinity than testosterone. 44 In some tissues, androgens help regulate the mTORC1 pathway through positive feedback loops.…”