ArticleThe EMBO journal2024
Disease-associated polyalanine expansion mutations impair UBA6-dependent ubiquitination.
Article in The EMBO journal, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers, 1 of them a synthesis that pooled it.
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Who cites it
8 citing papers in PubMed, 1 synthesis or guideline pooled it, 9 citations in OpenAlex.
- Pooled it
- Targeting UCHL3 attenuates pathological markers in neuronal models of Huntington's disease.Brain : a journal of neurology · 2026Article
- UBA6 serves as a prognostic biomarker and promotes tumor progression in pancreatic ductal adenocarcinoma.Translational cancer research · 2026Article
- The emerging importance of UBA6 in ubiquitylation and proteostasis.Nature reviews. Molecular cell biology · 2026Article
- UBA6 specificity for ubiquitin E2 conjugating enzymes reveals a priority mechanism of BIRC6.Nature structural & molecular biology · 2026Article
- CRISPR/Cas9-mediatedFrontiers in physiology · 2026Article
- Recent advances in recombinant production of soluble proteins in E. coli.Microbial cell factories · 2025Review
- A drug candidate for a rare polyalanine disease targeting the protein quality control.Molecular therapy. Nucleic acids · 2024Article
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
Abstract
Expansion mutations in polyalanine stretches are associated with a growing number of diseases sharing a high degree of genotypic and phenotypic commonality. These similarities prompted us to query the normal function of physiological polyalanine stretches and to investigate whether a common molecular mechanism is involved in these diseases. Here, we show that UBA6, an E1 ubiquitin-activating enzyme, recognizes a polyalanine stretch within its cognate E2 ubiquitin-conjugating enzyme USE1. Aberrations in this polyalanine stretch reduce ubiquitin transfer to USE1 and, subsequently, polyubiquitination and degradation of its target, the ubiquitin ligase E6AP. Furthermore, we identify competition for the UBA6-USE1 interaction by various proteins with polyalanine expansion mutations in the disease state. The deleterious interactions of expanded polyalanine tract proteins with UBA6 in mouse primary neurons alter the levels and ubiquitination-dependent degradation of E6AP, which in turn affects the levels of the synaptic protein Arc. These effects are also observed in induced pluripotent stem cell-derived autonomic neurons from patients with polyalanine expansion mutations, where UBA6 overexpression increases neuronal resilience to cell death. Our results suggest a shared mechanism for such mutations that may contribute to the congenital malformations seen in polyalanine tract diseases.
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