Actin is an evolutionarily-conserved damage-associated molecular pattern that signals tissue injury in Drosophila melanogaster

  1. Naren Srinivasan
  2. Oliver Gordon
  3. Susan Ahrens
  4. Anna Franz
  5. Safia Deddouche
  6. Probir Chakravarty
  7. David Phillips
  8. Ali A Yunus
  9. Michael K Rosen
  10. Rita S Valente
  11. Luis Teixeira
  12. Barry Thompson
  13. Marc S Dionne
  14. Will Wood
  15. Caetano Reis e Sousa  Is a corresponding author
  1. The Francis Crick Institute, United Kingdom
  2. Voisin Consulting Life Sciences, United Kingdom
  3. University of Bristol, United Kingdom
  4. Sanofi Strasbourg, France
  5. University of Texas Southwestern Medical Center, United States
  6. Instituto Gulbenkian de Ciência, Portugal
  7. Imperial College London, United Kingdom

Abstract

Damage associated molecular patterns (DAMPs) are released by dead cells and can trigger sterile inflammation and, in vertebrates, adaptive immunity. Actin is a DAMP detected in mammals by the receptor, DNGR-1, expressed by dendritic cells (DCs). DNGR-1 is phosphorylated by Src-family kinases and recruits the tyrosine kinase Syk to promote DC cross-presentation of dead cell-associated antigens. Here we report that actin is also a DAMP in invertebrates that lack DCs and adaptive immunity. Administration of actin to Drosophila melanogaster triggers a response characterised by selective induction of STAT target genes in the fat body through the cytokine Upd3 and its JAK/STAT-coupled receptor, Domeless. Notably, this response requires signalling via Shark, the Drosophila orthologue of Syk, and Src42A, a Drosophila Src-family kinase, and is dependent on Nox activity. Thus, extracellular actin detection via a Src-family kinase-dependent cascade is an ancient means of detecting cell injury that precedes evolution of adaptive immunity.

Data availability

The following data sets were generated
    1. Chakravarty P
    2. Srinivasan N
    (2016) Genome-wide responses to extracellular actin
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE76150).

Article and author information

Author details

  1. Naren Srinivasan

    Immunobiology Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Oliver Gordon

    Immunobiology Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Susan Ahrens

    Voisin Consulting Life Sciences, Camberly, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Anna Franz

    Department of Biochemistry, Biomedical Sciences, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Safia Deddouche

    Open Innovation Access Platform, Sanofi Strasbourg, Strasbourg, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Probir Chakravarty

    Bioinformatics, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. David Phillips

    Genomics-Equipment Park, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Ali A Yunus

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Michael K Rosen

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0775-7917
  10. Rita S Valente

    Instituto Gulbenkian de Ciência, Oeiras, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  11. Luis Teixeira

    Instituto Gulbenkian de Ciência, Oeiras, Portugal
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8326-6645
  12. Barry Thompson

    Epithelial Biology Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Marc S Dionne

    Department of Life Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Will Wood

    Department of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Caetano Reis e Sousa

    Immunobiology Laboratory, The Francis Crick Institute, London, United Kingdom
    For correspondence
    Caetano@crick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7392-2119

Funding

Wellcome (WT106973MA)

  • Caetano Reis e Sousa

Wellcome (FC001136)

  • Caetano Reis e Sousa

Medical Research Council (FC001136)

  • Caetano Reis e Sousa

Cancer Research UK (FC001136)

  • Caetano Reis e Sousa

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Zhijian J Chen, University of Texas Southwestern Medical School, United States

Publication history

  1. Received: July 14, 2016
  2. Accepted: November 14, 2016
  3. Accepted Manuscript published: November 22, 2016 (version 1)
  4. Version of Record published: December 5, 2016 (version 2)
  5. Version of Record updated: December 19, 2016 (version 3)

Copyright

© 2016, Srinivasan 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. Naren Srinivasan
  2. Oliver Gordon
  3. Susan Ahrens
  4. Anna Franz
  5. Safia Deddouche
  6. Probir Chakravarty
  7. David Phillips
  8. Ali A Yunus
  9. Michael K Rosen
  10. Rita S Valente
  11. Luis Teixeira
  12. Barry Thompson
  13. Marc S Dionne
  14. Will Wood
  15. Caetano Reis e Sousa
(2016)
Actin is an evolutionarily-conserved damage-associated molecular pattern that signals tissue injury in Drosophila melanogaster
eLife 5:e19662.
https://doi.org/10.7554/eLife.19662

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