Unravelling druggable signalling networks that control F508del-CFTR proteostasis

  1. Ramanath Narayana Hegde
  2. Seetharaman Parashuraman
  3. Francesco Iorio
  4. Fabiana Ciciriello
  5. Fabrizio Capuani
  6. Annamaria Carissimo
  7. Diego Carrella
  8. Vincenzo Belcastro
  9. Advait Subramanian
  10. Laura Bounti
  11. Maria Persico
  12. Graeme Carlile
  13. Luis Galietta
  14. David Y Thomas
  15. Diego Di Bernardo
  16. Alberto Luini  Is a corresponding author
  1. National Research Council, Italy
  2. European Molecular Biology Laboratory, European Bioinformatics Institute, United Kingdom
  3. Telethon Institute of Genetics and Medicine, Italy
  4. University of Rome, La Sapienza, Italy
  5. Institute of Protein Biochemistry, Italy
  6. KU Leuven University, Italy
  7. McGill University, Canada
  8. Institute of Giannina Gaslini, Italy

Abstract

Cystic fibrosis (CF) is caused by mutations in CF transmembrane conductance regulator (CFTR). The most frequent mutation (F508del-CFTR) results in altered proteostasis, i.e., in the misfolding and intracellular degradation of the protein. The F508del-CFTR proteostasis machinery and its homeostatic regulation are well studied, while the question whether 'classical' signalling pathways and phosphorylation cascades might control proteostasis remains barely explored. Here, we have unravelled signalling cascades acting selectively on the F508del-CFTR folding-trafficking defects by analysing the mechanisms of action of F508del-CFTR proteostasis regulator drugs through an approach based on transcriptional profiling followed by deconvolution of their gene signatures. Targeting multiple components of these signalling pathways resulted in potent and specific correction of F508del-CFTR proteostasis and in synergy with pharmacochaperones. These results provide new insights into the physiology of cellular proteostasis and a rational basis for developing effective pharmacological correctors of the F508del-CFTR defect.

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Author details

  1. Ramanath Narayana Hegde

    Institute of Protein Biochemistry, National Research Council, Naples, Italy
    Competing interests
    The authors declare that no competing interests exist.
  2. Seetharaman Parashuraman

    Institute of Protein Biochemistry, National Research Council, Naples, Italy
    Competing interests
    The authors declare that no competing interests exist.
  3. Francesco Iorio

    Wellcome Trust Genome Campus, European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Fabiana Ciciriello

    Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  5. Fabrizio Capuani

    Department of Physics, University of Rome, La Sapienza, Rome, Italy
    Competing interests
    The authors declare that no competing interests exist.
  6. Annamaria Carissimo

    Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  7. Diego Carrella

    Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  8. Vincenzo Belcastro

    Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  9. Advait Subramanian

    National Research Council, Institute of Protein Biochemistry, Naples, Italy
    Competing interests
    The authors declare that no competing interests exist.
  10. Laura Bounti

    KU Leuven University, Naples, Italy
    Competing interests
    The authors declare that no competing interests exist.
  11. Maria Persico

    Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  12. Graeme Carlile

    Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, Montréal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  13. Luis Galietta

    U.O.C. Genetica Medica, Institute of Giannina Gaslini, Genova, Italy
    Competing interests
    The authors declare that no competing interests exist.
  14. David Y Thomas

    Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, Montréal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  15. Diego Di Bernardo

    Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  16. Alberto Luini

    Institute of Protein Biochemistry, National Research Council, Naples, Italy
    For correspondence
    a.luini@ibp.cnr.it
    Competing interests
    The authors declare that no competing interests exist.

Copyright

© 2015, Hegde 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. Ramanath Narayana Hegde
  2. Seetharaman Parashuraman
  3. Francesco Iorio
  4. Fabiana Ciciriello
  5. Fabrizio Capuani
  6. Annamaria Carissimo
  7. Diego Carrella
  8. Vincenzo Belcastro
  9. Advait Subramanian
  10. Laura Bounti
  11. Maria Persico
  12. Graeme Carlile
  13. Luis Galietta
  14. David Y Thomas
  15. Diego Di Bernardo
  16. Alberto Luini
(2015)
Unravelling druggable signalling networks that control F508del-CFTR proteostasis
eLife 4:e10365.
https://doi.org/10.7554/eLife.10365

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https://doi.org/10.7554/eLife.10365

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