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  2. Phosphorylation of the compartmentalized PKA substrate TAF15 regulates RNA-protein interactions

Phosphorylation of the compartmentalized PKA substrate TAF15 regulates RNA-protein interactions

  • Cell Mol Life Sci. 2024 Apr 3;81(1):162. doi: 10.1007/s00018-024-05204-4.
Andreas Feichtner 1 2 Florian Enzler 3 Valentina Kugler 1 2 Katharina Hoppe 4 Sophia Mair 5 6 Leopold Kremser 7 Herbert Lindner 7 Roland G Huber 8 Ulrich Stelzl 9 Eduard Stefan 10 11 Omar Torres-Quesada 12 13
Affiliations

Affiliations

  • 1 Tyrolean Cancer Research Institute (TKFI), Innrain 66, 6020, Innsbruck, Austria.
  • 2 Institute of Molecular Biology and Center for Molecular Biosciences, University of Innsbruck, Technikerstrasse 25, 6020, Innsbruck, Austria.
  • 3 Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innrain 66/66a, 6020, Innsbruck, Austria.
  • 4 Institute of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innrain 80/82, 6020, Innsbruck, Austria.
  • 5 Department of Cardiac Surgery, Medical University of Innsbruck, Innrain 66/66a, 6020, Innsbruck, Austria.
  • 6 Vascage, Center of Clinical Stroke Research, 6020, Innsbruck, Austria.
  • 7 Division of Clinical Biochemistry, Biocenter, Medical University of Innsbruck, Innrain 80/82, 6020, Innsbruck, Austria.
  • 8 Bioinformatics Institute, Agency for Science Technology and Research, Singapore, 138671, Singapore.
  • 9 Institute of Pharmaceutical Sciences, University of Graz, Schubertstrasse 1, 8010, Graz, Austria.
  • 10 Tyrolean Cancer Research Institute (TKFI), Innrain 66, 6020, Innsbruck, Austria. eduard.stefan@uibk.ac.at.
  • 11 Institute of Molecular Biology and Center for Molecular Biosciences, University of Innsbruck, Technikerstrasse 25, 6020, Innsbruck, Austria. eduard.stefan@uibk.ac.at.
  • 12 Tyrolean Cancer Research Institute (TKFI), Innrain 66, 6020, Innsbruck, Austria. omar.torres-quesada@i-med.ac.at.
  • 13 Division of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Innrain 80/82, 6020, Innsbruck, Austria. omar.torres-quesada@i-med.ac.at.
Abstract

Spatiotemporal-controlled second messengers alter molecular interactions of central signaling nodes for ensuring physiological signal transmission. One prototypical second messenger molecule which modulates kinase signal transmission is the cyclic-adenosine monophosphate (cAMP). The main proteinogenic cellular effectors of cAMP are compartmentalized protein kinase A (PKA) complexes. Their cell-type specific compositions precisely coordinate substrate phosphorylation and proper signal propagation which is indispensable for numerous cell-type specific functions. Here we present evidence that TAF15, which is implicated in the etiology of amyotrophic lateral sclerosis, represents a novel nuclear PKA substrate. In cross-linking and immunoprecipitation experiments (iCLIP) we showed that TAF15 phosphorylation alters the binding to target transcripts related to mRNA maturation, splicing and protein-binding related functions. TAF15 appears to be one of multiple PKA substrates that undergo RNA-binding dynamics upon phosphorylation. We observed that the activation of the cAMP-PKA signaling axis caused a change in the composition of a collection of RNA species that interact with TAF15. This observation appears to be a broader principle in the regulation of molecular interactions, as we identified a significant enrichment of RNA-binding proteins within endogenous PKA complexes. We assume that phosphorylation of RNA-binding domains adds another layer of regulation to binary protein-RNAs interactions with consequences to RNA features including binding specificities, localization, abundance and composition.

Keywords

ALS; Affinity purification; Colon cancer; FET-protein; Interaction network; Molecular interactions; Neurodegeneration; Post-translational modification; Proteomics.

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