An autism-linked mutation disables phosphorylation control of UBE3A

Details

• Alternative Title:
  Cell
• Personal Author:
  Yi, Jason J. ; Berrios, Janet ; Newbern, Jason M. ; Snider, William D. ; Philpot, Benjamin D. ; Hahn, Klaus M. ; Zylka, Mark J.
• Description:
  Deletion of UBE3A causes the neurodevelopmental disorder Angelman syndrome (AS), while duplication or triplication of UBE3A is linked to autism. These genetic findings suggest that the ubiquitin ligase activity of UBE3A must be tightly maintained to promote normal brain development. Here, we found that protein kinase A (PKA) phosphorylates UBE3A in a region outside of the catalytic domain at residue T485 and inhibits UBE3A activity toward itself and other substrates. A de novo autism-linked missense mutation disrupts this phosphorylation site, causing enhanced UBE3A activity in vitro, enhanced substrate turnover in patient-derived cells, and excessive dendritic spine development in the brain. Our study identifies PKA as an upstream regulator of UBE3A activity and shows that an autism-linked mutation disrupts this phosphorylation control. Moreover, our findings implicate excessive UBE3A activity and the resulting synaptic dysfunction to autism pathogenesis.
• Subjects:
  Angelman Syndrome Animals Article Autistic Disorder Brain Cyclic AMP-Dependent Protein Kinases Dendritic Spines Embryo, Mammalian Enzyme Stability Female Humans Mice, Inbred C57BL Mutagenesis Mutation, Missense Phosphorylation Ubiquitin-Protein Ligases

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• Source:
  Cell. 162(4):795-807.
• Pubmed ID:
  26255772
• Pubmed Central ID:
  PMC4537845
• Document Type:
  Journal Article
• Funding:
  5P41EB002025/EB/NIBIB NIH HHS/United States ; DP1 ES024088/ES/NIEHS NIH HHS/United States ; DP1ES024088/DP/NCCDPHP CDC HHS/United States ; P01 GM103723/GM/NIGMS NIH HHS/United States ; P01-GM103723/GM/NIGMS NIH HHS/United States ; P30 HD003110/HD/NICHD NIH HHS/United States ; P30 NS045892/NS/NINDS NIH HHS/United States ; P30NS045892/NS/NINDS NIH HHS/United States ; P41 EB002025/EB/NIBIB NIH HHS/United States ; R01 MH093372/MH/NIMH NIH HHS/United States ; R01 NS031768/NS/NINDS NIH HHS/United States ; R01 NS085093/NS/NINDS NIH HHS/United States ; R01MH093372/MH/NIMH NIH HHS/United States ; R01NS085093/NS/NINDS NIH HHS/United States ; T32HD040127/HD/NICHD NIH HHS/United States ; U54 HD079124/HD/NICHD NIH HHS/United States ; U54HD079124/HD/NICHD NIH HHS/United States
• Volume:
  162
• Issue:
  4
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:457e17dbd33ce0dd86124fb9148da6e6bbd91a97057a6b0afb37b06bd7d6619d
• Download URL:
  https://stacks.cdc.gov/view/cdc/35194/cdc_35194_DS1.pdf
• File Type:
  [PDF - 2.90 MB ]