The Drosophila Chitinase-Like Protein IDGF3 Is Involved in Protection against Nematodes and in Wound Healing

Chitinase-like proteins (CLPs) of the 18 glycosyl hydrolase family retain structural similarity to chitinases but lack enzymatic activity. Although CLPs are upregulated in several human disorders that affect regenerative and inflammatory processes, very little is known about their normal physiological function. We show that an insect CLP (Drosophila imaginal disc growth factor 3, IDGF3) plays an immune-protective role during entomopathogenic nematode (EPN) infections. During these infections, nematodes force their entry into the host via border tissues, thus creating wounds. Whole-genome transcriptional analysis of nematode-infected wild-type and Idgf3 mutant larvae have shown that, in addition to the regulation of genes related to immunity and wound closure, IDGF3 represses Jak/STAT and Wingless signaling. Further experiments have confirmed that IDGF3 has multiple roles in innate immunity. It serves as an essential component required for the formation of hemolymph clots that seal wounds, and Idgf3 mutants display an extended developmental delay during wound healing. Altogether, our findings indicate that vertebrate and invertebrate CLP proteins function in analogous settings and have a broad impact on inflammatory reactions and infections. This opens the way to further genetic analysis of Drosophila IDGF3 and will help to elucidate the exact molecular context of CLP function.

[1]  J. C. Pastor-Pareja,et al.  Plasma membrane overgrowth causes fibrotic collagen accumulation and immune activation in Drosophila adipocytes , 2015, eLife.

[2]  S. Wasserman,et al.  An Effector Peptide Family Required for Drosophila Toll-Mediated Immunity , 2015, PLoS pathogens.

[3]  S. Hess,et al.  Recent proteomic advances in developmental, regeneration, and cancer governing signaling pathways , 2015, Proteomics.

[4]  C. Hunter,et al.  ParadYm shift: Ym1 and Ym2 as innate immunological regulators of IL-17 , 2014, Nature Immunology.

[5]  M. Freeman,et al.  PI3K Signaling and Stat92E Converge to Modulate Glial Responsiveness to Axonal Injury , 2014, PLoS biology.

[6]  R. Maizels,et al.  Chitinase-like proteins promote IL-17-mediated neutrophilia in a trade-off between nematode killing and host damage , 2014, Nature Immunology.

[7]  Buqu Hu,et al.  Chitinase 3–Like 1 Suppresses Injury and Promotes Fibroproliferative Responses in Mammalian Lung Fibrosis , 2014, Science Translational Medicine.

[8]  K. Kux,et al.  Tissue communication in regenerative inflammatory signaling: lessons from the fly gut , 2014, Front. Cell. Infect. Microbiol..

[9]  R. Markus,et al.  A Drosophila immune response against Ras-induced overgrowth , 2014, Biology Open.

[10]  I. Kounatidis,et al.  Drosophila as a model to study the role of blood cells in inflammation, innate immunity and cancer , 2014, Front. Cell. Infect. Microbiol..

[11]  A. Bejsovec,et al.  Pebble/ECT2 RhoGEF negatively regulates the Wingless/Wnt signaling pathway , 2013, Development.

[12]  J. C. Pastor-Pareja,et al.  Dissecting social cell biology and tumors using Drosophila genetics. , 2013, Annual review of genetics.

[13]  A. Spradling,et al.  Polyploidization and Cell Fusion Contribute to Wound Healing in the Adult Drosophila Epithelium , 2013, Current Biology.

[14]  P. Hyršl,et al.  Genome-Wide Transcriptional Analysis of Drosophila Larvae Infected by Entomopathogenic Nematodes Shows Involvement of Complement, Recognition and Extracellular Matrix Proteins , 2013, Journal of Innate Immunity.

[15]  Y. Modis,et al.  Chitinase 3-like 1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2 , 2013, Cell reports.

[16]  M. Miura,et al.  Homeostatic epithelial renewal in the gut is required for dampening a fatal systemic wound response in Drosophila. , 2013, Cell reports.

[17]  M. Fang,et al.  Bridging Decapentaplegic and Wingless signaling in Drosophila wings through repression of naked cuticle by Brinker , 2013, Development.

[18]  B. Alman,et al.  Cutaneous wound healing: recruiting developmental pathways for regeneration , 2012, Cellular and Molecular Life Sciences.

[19]  In-Hwan Jang,et al.  Genetic evidence of a redox‐dependent systemic wound response via Hayan Protease‐Phenoloxidase system in Drosophila , 2012, The EMBO journal.

[20]  W. Stec,et al.  Drosophila SOCS Proteins , 2011, Journal of signal transduction.

[21]  Susumu Goto,et al.  KEGG for integration and interpretation of large-scale molecular data sets , 2011, Nucleic Acids Res..

[22]  Paul Martin,et al.  Swatting flies: modelling wound healing and inflammation in Drosophila , 2011, Disease Models & Mechanisms.

[23]  T. Belenkaya,et al.  Sulfated is a negative feedback regulator of wingless in Drosophila , 2011, Developmental dynamics : an official publication of the American Association of Anatomists.

[24]  B. Ma,et al.  Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. , 2011, Annual review of physiology.

[25]  H. Herwald,et al.  Coagulation Systems of Invertebrates and Vertebrates and Their Roles in Innate Immunity: The Same Side of Two Coins? , 2010, Journal of Innate Immunity.

[26]  P. Hyršl,et al.  Clotting Factors and Eicosanoids Protect against Nematode Infections , 2010, Journal of Innate Immunity.

[27]  Michelle Cheng,et al.  Retinoids Regulate a Developmental Checkpoint for Tissue Regeneration in Drosophila , 2010, Current Biology.

[28]  P. Hyršl,et al.  Pathogen Entrapment by Transglutaminase—A Conserved Early Innate Immune Mechanism , 2010, PLoS pathogens.

[29]  Pavel Tomancak,et al.  A toolkit for high-throughput, cross-species gene engineering in Drosophila , 2009, Nature Methods.

[30]  N. Xu,et al.  Paracrine Wingless signalling controls self-renewal of Drosophila intestinal stem cells , 2008, Nature.

[31]  V. Hartenstein,et al.  The behaviour of Drosophila adult hindgut stem cells is controlled by Wnt and Hh signalling , 2008, Nature.

[32]  M. Dushay,et al.  Fondue and transglutaminase in the Drosophila larval clot. , 2008, Journal of insect physiology.

[33]  Robert M. Anthony,et al.  Protective immune mechanisms in helminth infection , 2007, Nature Reviews Immunology.

[34]  David S. Parker,et al.  CBP/p300 are bimodal regulators of Wnt signaling , 2007, The EMBO journal.

[35]  C. Hogaboam,et al.  Infectious disease, the innate immune response, and fibrosis. , 2007, The Journal of clinical investigation.

[36]  Dragana Rogulja,et al.  Regulation of Cell Proliferation by a Morphogen Gradient , 2005, Cell.

[37]  D. J. Olson,et al.  Shifted, the Drosophila ortholog of Wnt inhibitory factor-1, controls the distribution and movement of Hedgehog. , 2005, Developmental cell.

[38]  P. Loke,et al.  Chitinase and Fizz Family Members Are a Generalized Feature of Nematode Infection with Selective Upregulation of Ym1 and Fizz1 by Antigen-Presenting Cells , 2005, Infection and Immunity.

[39]  E. Verheyen,et al.  Nemo is an inducible antagonist of Wingless signaling during Drosophila wing development , 2004, Development.

[40]  L. Arckens,et al.  The instantly released Drosophila immune proteome is infection-specific. , 2004, Biochemical and biophysical research communications.

[41]  M. Dushay,et al.  Isolation and Characterization of Hemolymph Clotting Factors in Drosophila melanogaster by a Pullout Method , 2004, Current Biology.

[42]  G. Rubin,et al.  The Toll and Imd pathways are the major regulators of the immune response in Drosophila , 2002, The EMBO journal.

[43]  A. Llera,et al.  Crystal Structure of Imaginal Disc Growth Factor-2 , 2002, The Journal of Biological Chemistry.

[44]  M. Belvin,et al.  A genome-wide analysis of immune responses in Drosophila , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Paul T. Spellman,et al.  Genome-wide analysis of the Drosophila immune response by using oligonucleotide microarrays , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[46]  P J Bryant,et al.  A new family of growth factors produced by the fat body and active on Drosophila imaginal disc cells. , 1999, Development.

[47]  D. Mcnulty,et al.  An abundantly secreted glycoprotein from Drosophila melanogaster is related to mammalian secretory proteins produced in rheumatoid tissues and by activated macrophages. , 1995, Gene.

[48]  G. Rubin,et al.  dachshund encodes a nuclear protein required for normal eye and leg development in Drosophila. , 1994, Development.

[49]  M. Dushay,et al.  The Drosophila clotting system and its messages for mammals. , 2014, Developmental and comparative immunology.

[50]  Yan Wang,et al.  Using Drosophila larvae to study epidermal wound closure and inflammation. , 2013, Methods in molecular biology.

[51]  Pooja Mittal,et al.  A novel signaling pathway impact analysis , 2009, Bioinform..

[52]  M. Dushay,et al.  A role for Hemolectin in coagulation and immunity in Drosophila melanogaster. , 2007, Developmental and comparative immunology.