title: Triad3A regulates synaptic strength by ubiquitination of Arc.
abstract: Activity-dependent gene transcription and protein synthesis underlie many forms of learning-related synaptic plasticity. At excitatory glutamatergic synapses, the immediate early gene product Arc/Arg3.1 couples synaptic activity to postsynaptic endocytosis of AMPA-type glutamate receptors. Although the mechanisms for Arc induction have been described, little is known regarding the molecular machinery that terminates Arc function. Here, we demonstrate that the RING domain ubiquitin ligase Triad3A/RNF216 ubiquitinates Arc, resulting in its rapid proteasomal degradation. Triad3A associates with Arc, localizes to clathrin-coated pits, and is associated with endocytic sites in dendrites and spines. In the absence of Triad3A, Arc accumulates, leading to the loss of surface AMPA receptors. Furthermore, loss of Triad3A mimics and occludes Arc-dependent forms of synaptic plasticity. Thus, degradation of Arc by clathrin-localized Triad3A regulates the availability of synaptic AMPA receptors and temporally tunes Arc-mediated plasticity at glutamatergic synapses.
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Mabb
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA; Signature Research Program in Neuroscience and Behavior Disorders, Duke NUS Graduate Medical School Singapore, 8 College Road, Level 05-29, Singapore 169857, Singapore.
authors.forename: H Shawn
authors.initials: HS
authors.lastname: Je
authors.affiliation: School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Wall
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA; Janelia Farm Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA.
authors.forename: Camenzind G
authors.initials: CG
authors.lastname: Robinson
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Rylan S
authors.initials: RS
authors.lastname: Larsen
authors.affiliation: Signature Research Program in Neuroscience and Behavior Disorders, Duke NUS Graduate Medical School Singapore, 8 College Road, Level 05-29, Singapore 169857, Singapore.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qiang
authors.affiliation: School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Sonia A L
authors.initials: SA
authors.lastname: Corrêa
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA; Pfizer Worldwide Research and Development, Neuroscience Research Unit, Cambridge, MA 02139, USA. Electronic address: michael.ehlers@pfizer.com.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Ehlers
mesh_terms: D002966:Clathrin / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D002966:Clathrin; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; C092069:activity regulated cytoskeletal-associated protein; C458527:RNF216 protein, human; D044767:Ubiquitin-Protein Ligases