KIS counteracts PTBP2 and regulates alternative exon usage in neurons

  1. Marcos Moreno-Aguilera
  2. Alba M Neher
  3. Mónica B Mendoza
  4. Martin Dodel
  5. Faraz K Mardakheh
  6. Raúl Ortiz
  7. Carme Gallego  Is a corresponding author
  1. Molecular Biology Institute of Barcelona, Spain
  2. 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).

The following data sets were generated

Article and author information

Author details

  1. Marcos Moreno-Aguilera

    Molecular Biology Institute of Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5243-9582
  2. Alba M Neher

    Molecular Biology Institute of Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  3. Mónica B Mendoza

    Molecular Biology Institute of Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  4. Martin Dodel

    Centre for Cancer Cell and Molecular Biology, Queen Mary University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Faraz K Mardakheh

    Centre for Cancer Cell and Molecular Biology, Queen Mary University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3896-0827
  6. Raúl Ortiz

    Molecular Biology Institute of Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  7. Carme Gallego

    Molecular Biology Institute of Barcelona, Barcelona, Spain
    For correspondence
    cggbmc@ibmb.csic.es
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6961-3524

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.

Ethics

Animal experimentation: Animal experimental procedures were approved by the ethics committee of the Research Council of Spain (CSIC).

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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  1. Marcos Moreno-Aguilera
  2. Alba M Neher
  3. Mónica B Mendoza
  4. Martin Dodel
  5. Faraz K Mardakheh
  6. Raúl Ortiz
  7. Carme Gallego
(2024)
KIS counteracts PTBP2 and regulates alternative exon usage in neurons
eLife 13:e96048.
https://doi.org/10.7554/eLife.96048

Share this article

https://doi.org/10.7554/eLife.96048

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