Tissue Distribution of the Readthrough Isoform of AQP4 Reveals a Dual Role of AQP4ex Limited to CNS

Palazzo, Claudia; Abbrescia, Pasqua; Valente, Onofrio; Nicchia, Grazia Paola; Banitalebi, Shervin; Amiry-Moghaddam, Mahmood; Trojano, María; Frigeri, Antonio

doi:10.3390/ijms21041531

Cited by 19 publications

(13 citation statements)

References 39 publications

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“…More recently, several studies in Drosophila have reported highest levels of TR in tissues of the CNS, mainly neurons (Chen et al, 2020; Hudson et al, 2020). These studies are concurrent with findings in mice, where the incidence of cell-type-specific TR was detected by analysis of TR in neurons and astrocytes in the CNS as well as peripheral tissues (Palazzo et al, 2020; Sapkota et al, 2019). These observations, combined with significant overrepresentation of neuronal genes in bioinformatically predicted TR candidates (Jungreis et al, 2016; Jungreis et al, 2011) support the idea that elevated TR in susceptible genes might be an idiosyncratic feature of neuronal tissues, albeit the mechanism of such TR regulation remains completely unexplored.…”

Section: Discussionsupporting

confidence: 85%

Tissue-Specific Regulation of Translational Readthrough Tunes Functions of the Traffic Jam Transcription Factor

Karki

Carney

Maracci

et al. 2020

Preprint

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SummaryTranslational readthrough (TR) occurs when the ribosome decodes a stop codon as a sense codon, resulting in two protein isoforms synthesized from the same mRNA. TR is pervasive in eukaryotic organisms; however, its biological significance remains unclear. In this study, we quantify the TR potential of several candidate genes in Drosophila melanogaster and characterize the regulation of TR in the large Maf transcription factor Traffic jam (Tj). We used CRISPR/Cas9 generated mutant flies to show that the TR-generated Tj isoform is expressed in the nuclei of a subset of neural cells of the central nervous system and is excluded from the somatic cells of gonads, which express the short Tj isoform only. Translational control of TR is critical for preservation of neuronal integrity and maintenance of reproductive health. Fine-tuning of the gene regulatory functions of transcription factors by TR provides a new potential mechanism for cell-specific regulation of gene expression.HighlightsTj undergoes tissue-specific TR in neural cells of the central nervous system.Strict control of TR is crucial for neuroprotection and maintenance of reproductive capacity.TR selectively fine-tunes the gene regulatory functions of the transcription factor.TR in Tj links transcription and translation of tissue-specific control of gene expression.

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Section: Discussionsupporting

confidence: 85%

Tissue-Specific Regulation of Translational Readthrough Tunes Functions of the Traffic Jam Transcription Factor

Karki

Carney

Maracci

et al. 2020

Preprint

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“…As AQP4ex display a perivascular polarization and expression in dystrophin-dependent pools, it is necessary for anchoring of the perivascular AQP4. Indeed, the absence of AQP4ex isoform, AQP4 assemblies are mislocalized in the brain [64,65]. In the present study, we could not explore the alterations in AQP4 isoforms induced by 67LR neutralization and SE, since the commercial antibodies for AQP4 isoforms are unavailable.…”

Section: Discussionmentioning

confidence: 88%

Blockade of 67-kDa Laminin Receptor Facilitates AQP4 Down-Regulation and BBB Disruption via ERK1/2-and p38 MAPK-Mediated PI3K/AKT Activations

Kim

Park

Lee

et al. 2020

Cells

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Recently, we have reported that dysfunctions of 67-kDa laminin receptor (67LR) induced by status epilepticus (SE, a prolonged seizure activity) and 67LR neutralization are involved in vasogenic edema formation, accompanied by the reduced aquaporin 4 (AQP4, an astroglial specific water channel) expression in the rat piriform cortex (PC). In the present study, we found that the blockade of 67LR activated p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways, which enhanced phosphatidylinositol 3 kinase (PI3K)/AKT phosphorylations in endothelial cells and astrocytes, respectively. 67LR-p38 MAPK-PI3K-AKT activation in endothelial cells increased vascular permeability. In contrast, 67LR-ERK1/2-PI3K-AKT signaling pathways in astrocytes regulated astroglial viability and AQP4 expression. These findings indicate that PI3K/AKT may integrate p38 MAPK and ERK1/2 signaling pathways to regulate AQP4 expression when 67LR functionality is reduced. Thus, we suggest that 67LR-p38 MAPK/ERK1/2-PI3K-AKT-AQP4 signaling cascades may mediate serum extravasation and AQP4 expression in astroglio-vascular systems, which is one of the considerable therapeutic targets for vasogenic edema in various neurological diseases.

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“…Cell-type-specific regulation of readthrough was observed in mice using ribosome profiling (52), suggesting broader translational mechanisms that permit cell-type-specific readthrough in flies and mammals. Human AQP4 encodes an aquaporin that undergoes efficient stop codon readthrough in cell culture (14) and for which readthrough efficiency may be regulated in a tissue-specific manner (53).…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific dynamic codon redefinition in Drosophila

Hudson

Szabo

Loughran

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Translational stop codon readthrough occurs in organisms ranging from viruses to mammals and is especially prevalent in decoding Drosophila and viral mRNAs. Recoding of UGA, UAG, or UAA to specify an amino acid allows a proportion of the protein encoded by a single gene to be C-terminally extended. The extended product from Drosophila kelch mRNA is 160 kDa, whereas unextended Kelch protein, a subunit of a Cullin3-RING ubiquitin ligase, is 76 kDa. Previously we reported tissue-specific regulation of readthrough of the first kelch stop codon. Here, we characterize major efficiency differences in a variety of cell types. Immunoblotting revealed low levels of readthrough in malpighian tubules, ovary, and testis but abundant readthrough product in lysates of larval and adult central nervous system (CNS) tissue. Reporters of readthrough demonstrated greater than 30% readthrough in adult brains, and imaging in larval and adult brains showed that readthrough occurred in neurons but not glia. The extent of readthrough stimulatory sequences flanking the readthrough stop codon was assessed in transgenic Drosophila and in human tissue culture cells where inefficient readthrough occurs. A 99-nucleotide sequence with potential to form an mRNA stem-loop 3′ of the readthrough stop codon stimulated readthrough efficiency. However, even with just six nucleotides of kelch mRNA sequence 3′ of the stop codon, readthrough efficiency only dropped to 6% in adult neurons. Finally, we show that high-efficiency readthrough in the Drosophila CNS is common; for many neuronal proteins, C-terminal extended forms of individual proteins are likely relatively abundant.

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Tissue Distribution of the Readthrough Isoform of AQP4 Reveals a Dual Role of AQP4ex Limited to CNS

Cited by 19 publications

References 39 publications

Tissue-Specific Regulation of Translational Readthrough Tunes Functions of the Traffic Jam Transcription Factor

Tissue-Specific Regulation of Translational Readthrough Tunes Functions of the Traffic Jam Transcription Factor

Blockade of 67-kDa Laminin Receptor Facilitates AQP4 Down-Regulation and BBB Disruption via ERK1/2-and p38 MAPK-Mediated PI3K/AKT Activations

Tissue-specific dynamic codon redefinition in Drosophila

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