title: Actin is an evolutionarily-conserved damage-associated molecular pattern that signals tissue injury inDrosophila melanogaster.
abstract: Damage-associated molecular patterns (DAMPs) are molecules released by dead cells that 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 toDrosophila melanogastertriggers 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, theDrosophilaorthologue of Syk, and Src42A, aDrosophilaSrc-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 the evolution of adaptive immunity.
authors.affiliation: Immunobiology Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Naren
authors.initials: N
authors.lastname: Srinivasan
authors.affiliation: Immunobiology Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Oliver
authors.identifier: 0000-0002-2567-2482
authors.initials: O
authors.lastname: Gordon
authors.affiliation: Immunobiology Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Susan
authors.initials: S
authors.lastname: Ahrens
authors.affiliation: Department of Biochemistry, Biomedical Sciences, University Walk, University of Bristol, Bristol, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Franz
authors.affiliation: Immunobiology Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Safia
authors.initials: S
authors.lastname: Deddouche
authors.affiliation: Bioinformatics, The Francis Crick Institute, London, United Kingdom.
authors.forename: Probir
authors.initials: P
authors.lastname: Chakravarty
authors.affiliation: Genomics-Equipment Park, The Francis Crick Institute, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Phillips
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Ali A
authors.initials: AA
authors.lastname: Yunus
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Michael K
authors.identifier: 0000-0002-0775-7917
authors.initials: MK
authors.lastname: Rosen
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Rita S
authors.initials: RS
authors.lastname: Valente
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Luis
authors.identifier: 0000-0001-8326-6645
authors.initials: L
authors.lastname: Teixeira
authors.affiliation: Epithelial Biology Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Barry
authors.identifier: 0000-0002-0103-040X
authors.initials: B
authors.lastname: Thompson
authors.affiliation: Department of Life Sciences and MRC Centre for Molecular Bacteriology and Infection, South Kensington Campus, Imperial College London, London, United Kingdom.
authors.forename: Marc S
authors.identifier: 0000-0002-8283-1750
authors.initials: MS
authors.lastname: Dionne
authors.affiliation: Department of Cellular and Molecular Medicine, Biomedical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Will
authors.initials: W
authors.lastname: Wood
authors.affiliation: Immunobiology Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Caetano
authors.identifier: 0000-0001-7392-2119
authors.initials: C
authors.lastname: Reis e Sousa
mesh_terms: D000199:Actins / Q000378:metabolism*; D000067531:Alarmins / Q000378:metabolism*; D000818:Animals; D004331:Drosophila melanogaster / Q000502:physiology*; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: D000199:Actins; D000067531:Alarmins
keywords: D. melanogaster; DAMP; JAK/STAT pathway; damage-associated molecular pattern; immunology; innate immunity; sterile inflammation; tissue injury