Identification of intracellular cavin target proteins reveals cavin-PP1alpha interactions regulate apoptosis

Kerrie-Ann McMahon, Yeping Wu, Yann Gambin, Emma Sierecki, Vikas A. Tillu, Thomas Hall, Nick Martel, Satomi Okano, Shayli Varasteh Moradi, Jayde E. Ruelcke, Charles Ferguson, Alpha S. Yap, Kirill Alexandrov, Michelle M. Hill and Robert G. Parton ()
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Kerrie-Ann McMahon: The University of Queensland, Institute for Molecular Bioscience
Yeping Wu: The University of Queensland, Institute for Molecular Bioscience
Yann Gambin: The University of Queensland, Institute for Molecular Bioscience
Emma Sierecki: The University of Queensland, Institute for Molecular Bioscience
Vikas A. Tillu: The University of Queensland, Institute for Molecular Bioscience
Thomas Hall: The University of Queensland, Institute for Molecular Bioscience
Nick Martel: The University of Queensland, Institute for Molecular Bioscience
Satomi Okano: The University of Queensland, Institute for Molecular Bioscience
Shayli Varasteh Moradi: The University of Queensland, Institute for Molecular Bioscience
Jayde E. Ruelcke: The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Translational Research Institute
Charles Ferguson: The University of Queensland, Institute for Molecular Bioscience
Alpha S. Yap: The University of Queensland, Institute for Molecular Bioscience
Kirill Alexandrov: The University of Queensland, Institute for Molecular Bioscience
Michelle M. Hill: The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Translational Research Institute
Robert G. Parton: The University of Queensland, Institute for Molecular Bioscience

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract Caveolae are specialized domains of the plasma membrane. Formation of these invaginations is dependent on the expression of Caveolin-1 or -3 and proteins of the cavin family. In response to stress, caveolae disassemble and cavins are released from caveolae, allowing cavins to potentially interact with intracellular targets. Here, we describe the intracellular (non-plasma membrane) cavin interactome using biotin affinity proteomics and mass spectrometry. We validate 47 potential cavin-interactor proteins using a cell-free expression system and protein-protein binding assays. These data, together with pathway analyses, reveal unknown roles for cavin proteins in metabolism and stress signaling. We validated the interaction between one candidate interactor protein, protein phosphatase 1 alpha (PP1α), and Cavin-1 and -3 and show that UV treatment causes release of Cavin3 from caveolae allowing interaction with, and inhibition of, PP1α. This interaction increases H2AX phosphorylation to stimulate apoptosis, identifying a pro-apoptotic signaling pathway from surface caveolae to the nucleus.

Date: 2019
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DOI: 10.1038/s41467-019-11111-1

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