The autism susceptibility kinase, TAOK2, phosphorylates eEF2 and modulates translation
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Abstract
Genes implicated in translation control have been associated with autism spectrum disorders (ASDs). However, some important genetic causes of autism, including the 16p11.2 microdeletion, bear no obvious connection to translation. Here, we use proteomics, genetics, and translation assays in cultured cells and mouse brain to reveal altered translation mediated by loss of the kinase TAOK2 in 16p11.2 deletion models. We show that TAOK2 associates with the translational machinery and functions as a translational brake by phosphorylating eukaryotic elongation factor 2 (eEF2). Previously, all signal-mediated regulation of translation elongation via eEF2 phosphorylation was believed to be mediated by a single kinase, eEF2K. However, we show that TAOK2 can directly phosphorylate eEF2 on the same regulatory site, but functions independently of eEF2K signaling. Collectively, our results reveal an eEF2K-independent signaling pathway for control of translation elongation and suggest altered translation as a molecular component in the etiology of some forms of ASD.
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Cites
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- Authors
- Henis, M., Rücker, T., Scharrenberg, R., Richter, M., Baltussen, L., Hong, S., Meka, D. P., Schwanke, B., Neelagandan, N., Daaboul, D., Murtaza, N., Krisp, C., Harder, S., Schlüter, H., Kneussel, M., Hermans-Borgmeyer, I., de Wit, J., Singh, K. K., Duncan, K. E., & de Anda, F. C.
- Affiliations
- University Medical Center Hamburg-Eppendorf (DE)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- University Health Network (CA)
- Transgenic Service Group, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Falkenried 94, 20251 Hamburg, Germany.
- VIB Center for Brain & Disease Research, Herestraat 49, 3000 Leuven, Belgium.
- Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
- Corresponding author
- Henis, Melad
- Duncan, Kent E.
- ORCID
- Venue
- Science Advances
- Published
- 2024-04-12
- Volume
- 10
- Issue
- 15
- Pages
- eadf7001-eadf7001
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC11014455
- OpenAlex
- W4394743670
- Cited by
- 13
- References
- 10
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 4
- FWCI
- 1.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Science Advances (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Lirias (submittedVersion, cc-by-nc)
- Funders
- Gene Bridges
- Fonds Wetenschappelijk Onderzoek (12ZK221N)
- Cultural Affairs and Missions Sector, Ministry of Higher Education (2012-2017)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- TAOK2, eEF2 phosphorylation, eEF2K, translation elongation, autism spectrum disorder, 16p11.2 microdeletion, translational regulation, kinase signaling, mouse brain
- MeSH terms
- Autism Spectrum Disorder, Animals, Autistic Disorder, Ursidae, Biological Assay, Phosphorylation, Peptide Elongation Factor 2, Mice
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