ArticleThe Journal of biological chemistry2016
Destabilization of Atoh1 by E3 Ubiquitin Ligase Huwe1 and Casein Kinase 1 Is Essential for Normal Sensory Hair Cell Development.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 35 citations in OpenAlex.
- The ubiquitin-proteasome system and proteostasis in the cochlea and sensorineural hearing disorders.Molecular biomedicine · 2026Review
- Meis1 isoform diversity orchestrates neural progenitor differentiation by regulating ATOH1 degradation at distinct subcellular compartments.PLoS biology · 2026Article
- Dominant and recessive ATOH1 variants cause distinct neurodevelopmental disorders with hearing loss.American journal of human genetics · 2026Article
- Wnt/PKC Signaling Inhibits Sensory Hair Cell Formation in the Developing Mammalian Cochlea.Cells · 2025Article
- Sox2 interacts with Atoh1 and Huwe1 loci to regulate Atoh1 transcription and stability during hair cell differentiation.PLoS genetics · 2025Article
- Precise genetic control of ATOH1 enhances maturation of regenerated hair cells in the mature mouse utricle.Nature communications · 2024Article
- Pharmacological regeneration of sensory hair cells restores afferent innervation and vestibular function.The Journal of clinical investigation · 2024Article
- Article
- Gene therapy: an emerging therapy for hair cells regeneration in the cochlea.Frontiers in neuroscience · 2023Review
- Development and transdifferentiation into inner hair cells require Tbx2.National science review · 2022Article
- Three distinctProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Homodimeric and Heterodimeric Interactions among Vertebrate Basic Helix-Loop-Helix Transcription Factors.International journal of molecular sciences · 2021Review
- Cyclin D1 controls development of cerebellar granule cell progenitors through phosphorylation and stabilization of ATOH1.The EMBO journal · 2021Article
- A Screen of Autophagy Compounds Implicates the Proteasome in Mammalian Aminoglycoside-Induced Hair Cell Damage.Frontiers in cell and developmental biology · 2021Article
- Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1.Clinical genetics · 2020Article
- Merkel Cell Polyomavirus T Antigens Induce Merkel Cell-Like Differentiation in GLI1-Expressing Epithelial Cells.Cancers · 2020Article
- Prolyl hydroxylase 3 controls the intestine goblet cell generation through stabilizing ATOH1.Cell death and differentiation · 2020Article
- Using Sox2 to alleviate the hallmarks of age-related hearing loss.Ageing research reviews · 2020Review
- Roles of the HUWE1 ubiquitin ligase in nervous system development, function and disease.Neural development · 2020Review
- Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Proneural basic helix-loop-helix transcription factor, Atoh1, plays a key role in the development of sensory hair cells. We show here that the level of Atoh1 must be accurately controlled by degradation of the protein in addition to the regulation of Atoh1 gene expression to achieve normal cellular patterning during development of the cochlear sensory epithelium. The stability of Atoh1 was regulated by the ubiquitin proteasome system through the action of Huwe1, a HECT-domain, E3 ubiquitin ligase. An interaction between Huwe1 and Atoh1 could be visualized by a proximity ligation assay and was confirmed by co-immunoprecipitation and mass spectrometry. Transfer of a lysine 48-linked polyubiquitin chain to Atoh1 by Huwe1 could be demonstrated both in intact cells and in a cell-free system, and proteasome inhibition or Huwe1 silencing increased Atoh1 levels. The interaction with Huwe1 and polyubiquitylation were blocked by disruption of casein kinase 1 (CK1) activity, and mass spectrometry and mutational analysis identified serine 334 as an important phosphorylation site for Atoh1 ubiquitylation and subsequent degradation. Phosphorylation by CK1 thus targeted the protein for degradation. Development of an extra row of inner hair cells in the cochlea and an approximate doubling in the number of afferent synapses was observed after embryonic or early postnatal deletion of Huwe1 in cochlear-supporting cells, and hair cells died in the early postnatal period when Huwe1 was knocked out in the developing cochlea. These data indicate that the regulation of Atoh1 by the ubiquitin proteasome pathway is necessary for hair cell fate determination and survival.
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Registered trials
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