TY - JOUR
T1 - An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A
AU - Yi, Jason J.
AU - Berrios, Janet
AU - Newbern, Jason M.
AU - Snider, William D.
AU - Philpot, Benjamin D.
AU - Hahn, Klaus M.
AU - Zylka, Mark J.
N1 - Funding Information:
We thank Gabriela Salazar and Jayalakshmi Miriyala for technical assistance, Bonnie Taylor-Blake for help with confocal imaging, Yaohong Wu for help with in utero electroporations, David Smalley and Lee Graves for performing mass spectrometry analysis, Lei Xing for cortical lysates, and Rong Mao and Tatiana Tvrdik from The University of Utah and ARUP Laboratories for disclosing the UBE3A c.349T>C; p.C117R mutation. Immortalized lymphocytes from the Simons Simplex Collection were acquired from the NIMH Center for Genetic Studies via the Rutgers University Cell and DNA Repository. This work was supported by grants from the Angelman Syndrome Foundation (M.J.Z., B.D.P.), a Grant-In-Aid from the Foundation for Angelman Syndrome Therapeutics (M.J.Z.), The Simons Foundation (SFARI Award 274426, B.D.P.), the NIMH (R01MH093372; M.J.Z., B.D.P.), NINDS (R01NS085093, B.D.P.), a NIH Pioneer Award from The National Institutes of Health (DP1ES024088; M.J.Z.), the NIGMS (P01-GM103723; K.M.H.), and a Basic and Clinical Grant (#7760) from Autism Speaks (K.M.H.). J.J.Y. is a recipient of the Christina Castellana postdoctoral fellowship of the Foundation for Angelman Syndrome Therapeutics and was supported by NICHD (T32HD040127). The confocal imaging core was funded by grants from NINDS (P30NS045892) and NICHD (U54HD079124) and the CISMM imaging core in the Hahn lab by 5P41EB002025.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/8/17
Y1 - 2015/8/17
N2 - Summary 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.
AB - Summary 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.
UR - http://www.scopus.com/inward/record.url?scp=84939220718&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2015.06.045
DO - 10.1016/j.cell.2015.06.045
M3 - Article
C2 - 26255772
AN - SCOPUS:84939220718
VL - 162
SP - 795
EP - 807
JO - Cell
JF - Cell
SN - 0092-8674
IS - 4
M1 - 8292
ER -