title: Accumulation of nuclear ADAR2 regulates adenosine-to-inosine RNA editing during neuronal development.
abstract: Adenosine to inosine (A-to-I) RNA editing is important for a functional brain, and most known sites that are subject to selective RNA editing have been found to result in diversified protein isoforms that are involved in neurotransmission. In the absence of the active editing enzymes ADAR1 or ADAR2 (also known as ADAR and ADARB1, respectively), mice fail to survive until adulthood. Nuclear A-to-I editing of neuronal transcripts is regulated during brain development, with low levels of editing in the embryo and a dramatic increase after birth. Yet, little is known about the mechanisms that regulate editing during development. Here, we demonstrate lower levels of ADAR2 in the nucleus of immature neurons than in mature neurons. We show that importin-α4 (encoded byKpna3), which increases during neuronal maturation, interacts with ADAR2 and contributes to the editing efficiency by bringing it into the nucleus. Moreover, we detect an increased number of interactions between ADAR2 and the nuclear isomerase Pin1 as neurons mature, which contribute to ADAR2 protein stability. Together, these findings explain how the nuclear editing of substrates that are important for neuronal function can increase as the brain develops.
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Svante Arrheniusväg 20C, Stockholm, 106 91, Sweden.
authors.forename: Mikaela
authors.initials: M
authors.lastname: Behm
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Svante Arrheniusväg 20C, Stockholm, 106 91, Sweden.
authors.forename: Helene
authors.initials: H
authors.lastname: Wahlstedt
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Svante Arrheniusväg 20C, Stockholm, 106 91, Sweden.
authors.forename: Albin
authors.initials: A
authors.lastname: Widmark
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Svante Arrheniusväg 20C, Stockholm, 106 91, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Eriksson
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Svante Arrheniusväg 20C, Stockholm, 106 91, Sweden marie.ohman@su.se.
authors.forename: Marie
authors.identifier: 0000-0002-6636-5841
authors.initials: M
authors.lastname: Öhman
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D057809:HEK293 Cells; D006801:Humans; D007288:Inosine / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000378:metabolism; D011485:Protein Binding; D017393:RNA Editing; D051381:Rats; D028901:alpha Karyopherins
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019913:Nuclear Localization Signals; D028901:alpha Karyopherins; C568791:importin alpha4, mouse; D007288:Inosine; C000602621:Adarb1 protein, rat; D000243:Adenosine Deaminase; C000606850:Pin1 protein, mouse; D000241:Adenosine
keywords: A-to-I RNA editing; ADAR2; Importin-α4; Pin1