title: Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects.
abstract: ADAR2 catalyses the deamination of adenosine to inosine at the GluR2 Q/R site in the pre-mRNA encoding the critical subunit of AMPA receptors. Among ADAR2 substrates this is the vital one as editing at this position is indispensable for normal brain function. However, the regulation of ADAR2 post-translationally remains to be elucidated. We demonstrate that the phosphorylation-dependent prolyl-isomerase Pin1 interacts with ADAR2 and is a positive regulator required for the nuclear localization and stability of ADAR2. Pin1(-/-) mouse embryonic fibroblasts show mislocalization of ADAR2 in the cytoplasm and reduced editing at the GluR2 Q/R and R/G sites. The E3 ubiquitin ligase WWP2 plays a negative role by binding to ADAR2 and catalysing its ubiquitination and subsequent degradation. Therefore, ADAR2 protein levels and catalytic activity are coordinately regulated in a positive manner by Pin1 and negatively by WWP2 and this may have downstream effects on the function of GluR2. Pin1 and WWP2 also regulate the large subunit of RNA Pol II, so these proteins may also coordinately regulate other key cellular proteins.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors.forename: Roberto
authors.initials: R
authors.lastname: Marcucci
authors.forename: James
authors.initials: J
authors.lastname: Brindle
authors.forename: Simona
authors.initials: S
authors.lastname: Paro
authors.forename: Angela
authors.initials: A
authors.lastname: Casadio
authors.forename: Sophie
authors.initials: S
authors.lastname: Hempel
authors.forename: Nicholas
authors.initials: N
authors.lastname: Morrice
authors.forename: Andrea
authors.initials: A
authors.lastname: Bisso
authors.forename: Liam P
authors.initials: LP
authors.lastname: Keegan
authors.forename: Giannino
authors.initials: G
authors.lastname: Del Sal
authors.forename: Mary A
authors.initials: MA
authors.lastname: O'Connell
mesh_terms: D000243:Adenosine Deaminase / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D051379:Mice; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D017393:RNA Editing; D012319:RNA Polymerase II / Q000378:metabolism; D016601:RNA-Binding Proteins; D018091:Receptors, AMPA / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016601:RNA-Binding Proteins; D018091:Receptors, AMPA; C487995:Wwp2 protein, mouse; D044767:Ubiquitin-Protein Ligases; D012319:RNA Polymerase II; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; C104722:glutamate receptor ionotropic, AMPA 2