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PMID: 21847096 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects.

The EMBO journal ·Vol. 30 ·No. 20 ·2011-08-16 ·Pages 4211-22

Marcucci R, Brindle J, Paro S, Casadio A, Hempel S, Morrice N, Bisso A, Keegan LP, Del Sal G, O'Connell MA

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.

MeSH Terms
Adenosine Deaminase/metabolism Animals Cell Line Fibroblasts/metabolism Mice NIMA-Interacting Peptidylprolyl Isomerase Peptidylprolyl Isomerase/metabolism RNA Editing RNA Polymerase II/metabolism RNA-Binding Proteins Receptors, AMPA/metabolism Ubiquitin-Protein Ligases/metabolism Ubiquitination
Chemicals
NIMA-Interacting Peptidylprolyl Isomerase RNA-Binding Proteins Receptors, AMPA Wwp2 protein, mouse Ubiquitin-Protein Ligases RNA Polymerase II ADARB1 protein, human Adenosine Deaminase PIN1 protein, human Peptidylprolyl Isomerase Pin1 protein, mouse glutamate receptor ionotropic, AMPA 2
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Marcucci Roberto
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
Brindle James
Paro Simona
Casadio Angela
Hempel Sophie
Morrice Nicholas
Bisso Andrea
Keegan Liam P
Del Sal Giannino
O'Connell Mary A
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2011.303
Published
2011-08-16
Epub
2011-00-16
Pages
4211-22
Language
English
Region
England
NLM ID
8208664
PMCID
PMC3199391
Subset
IM
Grants
Telethon · GGP07185 · Italy
Medical Research Council · MC_U127584490 · United Kingdom
Medical Research Council · U.1275.01.005.00001.01 · United Kingdom
External Links
PubMed source DOI: 10.1038/emboj.2011.303 PMC Full Text View journal details
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