KIS counteracts PTBP2 and regulates alternative exon usage in neurons
- Molecular Biology Institute of Barcelona, Spain
- Queen Mary University of London, United Kingdom
Abstract
Alternative RNA splicing is an essential and dynamic process in neuronal differentiation and synapse maturation, and dysregulation of this process has been associated with neurodegenerative diseases. Recent studies have revealed the importance of RNA-binding proteins in the regulation of neuronal splicing programs. However, the molecular mechanisms involved in the control of these splicing regulators are still unclear. Here we show that KIS, a kinase upregulated in the developmental brain, imposes a genome-wide alteration in exon usage during neuronal differentiation in mice. KIS contains a protein-recognition domain common to spliceosomal components and phosphorylates PTBP2, counteracting the role of this splicing factor in exon exclusion. At the molecular level, phosphorylation of unstructured domains within PTBP2 causes its dissociation from two co-regulators, Matrin3 and hnRNPM, and hinders the RNA-binding capability of the complex. Furthermore, KIS and PTBP2 display strong and opposing functional interactions in synaptic spine emergence and maturation. Taken together, our data uncover a post-translational control of splicing regulators that link transcriptional and alternative exon usage programs in neuronal development.
Data availability
-The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium through the PRIDE partner repository (PXD050320).- RNA-seq fastq files and read summaries are available from GEO (GSE260790).
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KIS counteracts PTBP2 and regulates alternative exon usage in neuronsNCBI Gene Expression Omnibus, GSE260790.
Article and author information
Author details
Marcos Moreno-Aguilera
Funding
Ministerio de Ciencia e Innovación (PRE2018-083268)
- Mónica B Mendoza
Ministerio de Ciencia e Innovación (PID2020-113231GB-I00)
- Carme Gallego
Medical Research Council (MR/P009417/1)
- Faraz K Mardakheh
Barts Charity (MGU0346)
- Faraz K Mardakheh
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jens Lüders, Institute for Research in Biomedicine, Spain
Ethics
Animal experimentation: Animal experimental procedures were approved by the ethics committee of the Research Council of Spain (CSIC).
Version history
- Preprint posted: May 15, 2023 (view preprint)
- Received: January 12, 2024
- Accepted: April 9, 2024
- Accepted Manuscript published: April 10, 2024 (version 1)
- Version of Record published: April 25, 2024 (version 2)
Copyright
© 2024, Moreno-Aguilera et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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KIS counteracts PTBP2 and regulates alternative exon usage in neurons
eLife 13:e96048.
https://doi.org/10.7554/eLife.96048
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