Accumulation of nuclear ADAR2 regulates adenosine-to-inosine RNA editing during neuronal development

Behm, Mikaela; Wahlstedt, Helene; Widmark, Albin; Eriksson, Maria; Öhman, Marie

doi:10.1242/jcs.200055

Cited by 60 publications

(62 citation statements)

References 46 publications

(67 reference statements)

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“…Recently, it was shown that in developing mouse neurons increased nuclear localization of ADAR2 might contribute to this phenomenon [29] together with protein modifications on ADARs and regulatory factors [30,31]. We previously showed that a gradual increase in editing is also found for filamin A, in both neuronal and non-neuronal tissues [20].…”

Section: Discussionmentioning

confidence: 99%

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

et al. 2018

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Adenosine to inosine RNA editing in protein-coding messenger RNAs (mRNAs) potentially leads to changes in the amino acid composition of the encoded proteins. The mRNAs encoding the ubiquitously expressed actin-crosslinking proteins Filamin A and Filamin B undergo RNA editing leading to a highly conserved glutamine to arginine exchange at the identical position in either protein. Here, by targeted amplicon sequencing we analysed the RNA editing of Filamin B across several mouse tissues during post-natal development. We find highest filamin B editing levels in skeletal muscles, cartilage and bones, tissues where Filamin B function seems most important. Through the analysis of Filamin B editing in mice deficient in either ADAR1 or 2, we identified ADAR2 as the enzyme responsible for Filamin B RNA editing. We show that in neuronal tissues Filamin B editing drops in spliced transcripts indicating regulated maturation of edited transcripts. We show further that the variability of Filamin B editing across several organs correlates with its mRNA expression.

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Section: Discussionmentioning

confidence: 99%

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

et al. 2018

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“…The recently identified ADAR binding partners, ELAVL1, DHX9 and SRSF9 have also been shown to affect the editing level of specific sites (Aktaş et al, 2017; Huang et al, 2018; Shanmugam et al, 2018; Stellos et al, 2016). In addition to site-specific regulators of editing, Pin1, WWP2 and AIMP2 have been shown to regulate editing through post-translational modification of the ADAR proteins (Behm et al, 2017; Marcucci et al, 2011; Tan et al, 2017). However, the complexity of editing level regulation across millions of editing sites in numerous tissues and developmental stages suggests that there are likely many other proteins that regulate editing.…”

Section: Introductionmentioning

confidence: 99%

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

Freund

Sapiro

et al. 2019

Preprint

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13Adenosine-to-Inosine RNA editing is catalyzed by ADAR enzymes that deaminate adenosine to 14 inosine. While many RNA editing sites are known, few trans regulators have been identified. We 15 perform BioID followed by mass-spectrometry to identify trans regulators of ADAR1 and ADAR2 16 in HeLa and M17 neuroblastoma cells. We identify known and novel ADAR-interacting proteins. 17Using ENCODE data we validate and characterize a subset of the novel interactors as global or 18 site-specific RNA editing regulators. Our set of novel trans regulators includes all four members 19 of the DZF-domain-containing family of proteins: ILF3, ILF2, STRBP, and ZFR. We show that 20 these proteins interact with each ADAR and modulate RNA editing levels. We find ILF3 is a 21 global negative regulator of editing. This work demonstrates the broad roles RNA binding 22 proteins play in regulating editing levels and establishes DZF-domain containing proteins as a 23 group of highly influential RNA editing regulators. 24 25 47 the majority of ADAR1-regulated editing sites are found in repeat regions, ADAR2 is primarily 48 responsible for editing adenosines found in non-repeat regions, particularly in the brain (Tan et 49 al., 2017). ADAR2-regulated sites in non-repetitive regions include a number of editing events 50 that alter the protein-coding sequences of neuronal RNAs, including GluR2, which encodes a 51 glutamate receptor in which RNA editing is necessary for its proper function. Further 52 demonstrating its important role in neuronal editing, dysregulation of human ADAR2 is 53 associated with multiple neurological diseases, including amyotrophic lateral sclerosis, 54 astrocytoma and transient forebrain ischemia (Slotkin and Nishikura, 2013; Tran et al., 2019). 55Maintaining RNA editing levels is critical for human health, but how RNA editing levels are 56 regulated at specific editing sites across tissues and development is poorly understood. 58While RNA sequence and structure are critical determinants of editing levels, studies querying 59 tissue-specific and developmental-stage-specific editing levels show that the level of editing at 60 the same editing site can vary greatly between individuals and tissues. These changes do not 61 always correlate with ADAR mRNA or protein expression, suggesting a complex regulation of 62 editing events by factors other than ADAR proteins (Sapiro et al., 2019; Tan et al., 2017; 63 Wahlstedt et al., 2009). Recently, an analysis of proteins with an RNA-binding domain profiled 64 by ENCODE suggested that RNA-binding proteins play a role in RNA editing regulation. Further, 65 in mammals, a small number of trans regulators of editing have been identified through 66 functional experiments (Quinones-Valdez et al., 2019). Some of these trans regulators of editing 67 are site-specific, in that they affect editing levels at only a small subset of editing sites. These 68 include RNA binding proteins such as DHX15, HNRNPA2/B1, RPS14, TDP-43, Drosha and 69 Ro60 (Garncarz et al., 2013; Quinones-Valdez ...

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“…Loss of the ADAR2-Pin1 interaction leads to ADAR2 export into cytosol where it is ubiquitinated and degraded (32). Pin1 mediated stabilisation is important for ADAR2 editing activity during development in cortical neurons (11). However, our experiments suggest Pin1-ADAR2 interactions do not play a role in TTX up-scaling since both phosphonull and phosphomimetic mutants of ADAR2, which decrease or enhance binding to Pin1 respectively, were equally susceptible to the TTX mediated loss.…”

Section: Differential Sensitivity Of Gluk2 To Changes In Adar2 Levelsmentioning

confidence: 60%

“…ADAR2 levels are very low during embryogenesis but increase in the first postnatal week (11) to edit ~80% of GluK2, ~40% of GluK1 and ~99% of GluA2 subunits in the mature brain (12)(13)(14). ADAR2 knockout mice die at the early postnatal stage, but can be rescued by expressing the edited form of GluA2, demonstrating that unedited AMPARs are fatally excitotoxic (15).…”

Section: Introductionmentioning

confidence: 99%

ADAR2 mediated Q/R editing of GluK2 regulates homeostatic plasticity of kainate receptors

Gurung

Evans

Wilkinson

et al. 2018

Preprint

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Kainate receptors (KARs) are heteromeric glutamate-gated ion channels that regulate neuronal excitability and network function in the brain. Most KARs contain the subunit GluK2 and the precise properties of these GluK2-containing KARs are determined by additional factors including ADAR2mediated mRNA editing of a single codon that changes a genomically encoded glutamine (Q) to arginine (R) in the pore-lining region of GluK2. ADAR2-dependent Q/R editing of GluK2 is dynamically regulated during homeostatic plasticity (scaling) elicited by suppression of synaptic activity with TTX. Here we show that TTX decreases levels of ADAR2 by enhancing its proteasomal degradation. This selectively reduces the numbers of GluK2 subunits that are edited and increases the surface expression of GluK2-containing KARs. Furthermore, we show that partial ADAR2 knockdown phenocopies and occludes TTX-induced scaling of KARs. These data indicate that activity-dependent regulation of ADAR2 proteostasis and GluK2 Q/R editing provides a mechanism for KAR homeostatic plasticity. KeywordsSynapse, Kainate receptor, AMPA receptor, GluK2, ADAR2, mRNA editing, homeostatic plasticity, scaling. S c r a m b le d P a r t ia l A D A R 2 K D

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Accumulation of nuclear ADAR2 regulates adenosine-to-inosine RNA editing during neuronal development

Cited by 60 publications

References 46 publications

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

ADAR2 mediated Q/R editing of GluK2 regulates homeostatic plasticity of kainate receptors

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