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A 5′ UTR GGN repeat controls localisation and translation of a potassium leak channel mRNA through G-quadruplex formation

A 5′ UTR GGN repeat controls localisation and translation of a potassium leak channel mRNA through G-quadruplex formation
A 5′ UTR GGN repeat controls localisation and translation of a potassium leak channel mRNA through G-quadruplex formation
RNA G-quadruplexes (G4s) are secondary structures proposed to function as regulators of post-transcriptional mRNA localisation and translation. G4s within some neuronal mRNAs are known to control distal localisation and local translation, contributing to distinct local proteomes that facilitate the synaptic remodelling attributed to normal cellular function. In this study, we characterise the G4 formation of a (GGN)13 repeat found within the 5′ UTR of the potassium 2-pore domain leak channel Task3 mRNA. Biophysical analyses show that this (GGN)13 repeat forms a parallel G4 in vitro exhibiting the stereotypical potassium specificity of G4s, remaining thermostable under physiological ionic conditions. Through mouse brain tissue G4-RNA immunoprecipitation, we further confirm that Task3 mRNA forms a G4 structure in vivo. The G4 is inhibitory to translation of Task3 in vitro and is overcome through activity of a G4-specific helicase DHX36, increasing K+ leak currents and membrane hyperpolarisation in HEK293 cells. Further, we observe that this G4 is fundamental to ensuring delivery of Task3 mRNA to distal primary cortical neurites. It has been shown that aberrant Task3 expression correlates with neuronal dysfunction, we therefore posit that this G4 is important in regulated local expression of Task3 leak channels that maintain K+ leak within neurons.
0305-1048
9822-9839
Maltby, Connor
785e7b68-509e-450f-8b0c-7d8e46db58a7
Schofield, James
529d3c88-857e-4431-93c2-e76577377ba7
Houghton, Steven
b7d64445-1c7a-4b7e-87e4-98978460fc6e
O'Kelly, Ita
e640f28a-42f0-48a6-9ce2-cb5a85d08c66
Vargas-Caballero, Mariana
de2178ac-77fd-4748-9fe5-109ab8ad93e1
Deinhardt, Katrin
5f4fe23b-2317-499f-ba6d-e639a4885dc1
Coldwell, Mark
a3432799-ed45-4948-9f7a-2a284d3ec65c
Maltby, Connor
785e7b68-509e-450f-8b0c-7d8e46db58a7
Schofield, James
529d3c88-857e-4431-93c2-e76577377ba7
Houghton, Steven
b7d64445-1c7a-4b7e-87e4-98978460fc6e
O'Kelly, Ita
e640f28a-42f0-48a6-9ce2-cb5a85d08c66
Vargas-Caballero, Mariana
de2178ac-77fd-4748-9fe5-109ab8ad93e1
Deinhardt, Katrin
5f4fe23b-2317-499f-ba6d-e639a4885dc1
Coldwell, Mark
a3432799-ed45-4948-9f7a-2a284d3ec65c

Maltby, Connor, Schofield, James, Houghton, Steven, O'Kelly, Ita, Vargas-Caballero, Mariana, Deinhardt, Katrin and Coldwell, Mark (2020) A 5′ UTR GGN repeat controls localisation and translation of a potassium leak channel mRNA through G-quadruplex formation. Nucleic Acids Research, 48 (17), 9822-9839, [gkaa699]. (doi:10.1093/nar/gkaa699).

Record type: Article

Abstract

RNA G-quadruplexes (G4s) are secondary structures proposed to function as regulators of post-transcriptional mRNA localisation and translation. G4s within some neuronal mRNAs are known to control distal localisation and local translation, contributing to distinct local proteomes that facilitate the synaptic remodelling attributed to normal cellular function. In this study, we characterise the G4 formation of a (GGN)13 repeat found within the 5′ UTR of the potassium 2-pore domain leak channel Task3 mRNA. Biophysical analyses show that this (GGN)13 repeat forms a parallel G4 in vitro exhibiting the stereotypical potassium specificity of G4s, remaining thermostable under physiological ionic conditions. Through mouse brain tissue G4-RNA immunoprecipitation, we further confirm that Task3 mRNA forms a G4 structure in vivo. The G4 is inhibitory to translation of Task3 in vitro and is overcome through activity of a G4-specific helicase DHX36, increasing K+ leak currents and membrane hyperpolarisation in HEK293 cells. Further, we observe that this G4 is fundamental to ensuring delivery of Task3 mRNA to distal primary cortical neurites. It has been shown that aberrant Task3 expression correlates with neuronal dysfunction, we therefore posit that this G4 is important in regulated local expression of Task3 leak channels that maintain K+ leak within neurons.

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More information

Accepted/In Press date: 28 August 2020
e-pub ahead of print date: 1 September 2020
Published date: 25 September 2020

Identifiers

Local EPrints ID: 443961
URI: http://eprints.soton.ac.uk/id/eprint/443961
ISSN: 0305-1048
PURE UUID: 3d825c15-f370-47e7-9a5a-9de7cfb81055
ORCID for Mariana Vargas-Caballero: ORCID iD orcid.org/0000-0003-2326-4001
ORCID for Katrin Deinhardt: ORCID iD orcid.org/0000-0002-6473-5298
ORCID for Mark Coldwell: ORCID iD orcid.org/0000-0002-6243-3886

Catalogue record

Date deposited: 18 Sep 2020 16:30
Last modified: 17 Mar 2021 02:44

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