Unusual regulation of a STAT protein by an SLC6 family transporter in C. elegans epidermal innate immunity.

The cuticle and epidermis of Caenorhabditis elegans provide the first line of defense against invading pathogens. Upon invasion by the fungal pathogen Drechmeria coniospora, C. elegans responds by upregulating the expression of antimicrobial peptides (AMPs) in the epidermis via activation of at least two pathways, a neuroendocrine TGF-β pathway and a p38 MAPK pathway. Here, we identify the sodium-neurotransmitter symporter SNF-12, a member of the solute carrier family (SLC6), as being essential for both these immune signaling pathways. We also identify the STAT transcription factor-like protein STA-2 as a direct physical interactor of SNF-12 and show that the two proteins function together to regulate AMP gene expression in the epidermis. Both SNF-12 and STA-2 act cell autonomously and specifically in the epidermis to govern the transcriptional response to fungal infection. These findings reveal an unorthodox mode of regulation for a STAT factor and highlight the molecular plasticity of innate immune signaling.

[1]  F. Ausubel,et al.  Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[2]  P. Sehgal.  Paradigm shifts in the cell biology of STAT signaling. , 2008, Seminars in cell & developmental biology.

[3]  N. Hacohen,et al.  Evolutionarily conserved recognition and innate immunity to fungal pathogens by the scavenger receptors SCARF1 and CD36 , 2009, The Journal of experimental medicine.

[4]  S. Elledge,et al.  BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3 , 2003, Nature.

[5]  N. Perrimon,et al.  Sequential activation of signaling pathways during innate immune responses in Drosophila. , 2002, Developmental cell.

[6]  Trupti Kawli,et al.  Neuroendocrine signals modulate the innate immunity of Caenorhabditis elegans through insulin signaling , 2008, Nature Immunology.

[7]  Theresa Stiernagle.  Maintenance of C. elegans. , 2006, WormBook : the online review of C. elegans biology.

[8]  Shigeki Watanabe,et al.  Differential requirements for clathrin in receptor-mediated endocytosis and maintenance of synaptic vesicle pools , 2009, Proceedings of the National Academy of Sciences.

[9]  M. Labouesse,et al.  The V0-ATPase mediates apical secretion of exosomes containing Hedgehog-related proteins in Caenorhabditis elegans , 2006, The Journal of cell biology.

[10]  J. Bromberg.  Activation of STAT proteins and growth control , 2001, BioEssays : news and reviews in molecular, cellular and developmental biology.

[11]  Valerie Reinke,et al.  p38 MAPK Regulates Expression of Immune Response Genes and Contributes to Longevity in C. elegans , 2006, PLoS genetics.

[12]  Andrew D. Chisholm,et al.  Distinct Innate Immune Responses to Infection and Wounding in the C. elegans Epidermis , 2008, Current Biology.

[13]  M. Koelle,et al.  Biogenic amine neurotransmitters in C. , 2007 .

[14]  J. Hodgkin,et al.  Signal transduction pathways that function in both development and innate immunity , 2010, Developmental dynamics : an official publication of the American Association of Anatomists.

[15]  Frederick M. Ausubel,et al.  Evolution of host innate defence: insights from Caenorhabditis elegans and primitive invertebrates , 2010, Nature Reviews Immunology.

[16]  M. Labouesse,et al.  Assembly of C. elegans apical junctions involves positioning and compaction by LET-413 and protein aggregation by the MAGUK protein DLG-1. , 2001, Journal of cell science.

[17]  N. Pujol,et al.  Antifungal innate immunity in C. elegans: PKCdelta links G protein signaling and a conserved p38 MAPK cascade. , 2009, Cell host & microbe.

[18]  Y. Kohara,et al.  TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM , 2004, Nature Immunology.

[19]  J. Reboul,et al.  A genome-wide study of PDZ-domain interactions in C. elegans reveals a high frequency of non-canonical binding , 2010, BMC Genomics.

[20]  Frederick M. Ausubel,et al.  bZIP transcription factor zip-2 mediates an early response to Pseudomonas aeruginosa infection in Caenorhabditis elegans , 2010, Proceedings of the National Academy of Sciences.

[21]  D. Levy,et al.  C. elegans STAT: evolution of a regulatory switch , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  H. Melikian.  Neurotransmitter transporter trafficking: endocytosis, recycling, and regulation. , 2004, Pharmacology & therapeutics.

[23]  C. Rubin,et al.  Protein kinase D is an essential regulator of C. elegans innate immunity. , 2009, Immunity.

[24]  Dennis H Kim,et al.  Transcriptional responses to pathogens in Caenorhabditis elegans. , 2008, Current opinion in microbiology.

[25]  M. Shapira,et al.  Caenorhabditis elegans pgp-5 is involved in resistance to bacterial infection and heavy metal and its regulation requires TIR-1 and a p38 map kinase cascade. , 2007, Biochemical and biophysical research communications.

[26]  T. Hunter,et al.  The protein kinases of Caenorhabditis elegans: a model for signal transduction in multicellular organisms. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Nektarios Tavernarakis,et al.  Genome-wide investigation reveals pathogen-specific and shared signatures in the response of Caenorhabditis elegans to infection , 2007, Genome Biology.

[28]  Min Han,et al.  The fatty acid synthase fasn-1 acts upstream of WNK and Ste20/GCK-VI kinases to modulate antimicrobial peptide expression in C. elegans epidermis , 2010, Virulence.

[29]  M. Koelle,et al.  Biogenic amine neurotransmitters in C. elegans. , 2007, WormBook : the online review of C. elegans biology.

[30]  T. Maniatis,et al.  Endocytic pathway is required for Drosophila Toll innate immune signaling , 2010, Proceedings of the National Academy of Sciences.

[31]  J. Vandekerckhove,et al.  unc-53 controls longitudinal migration in C. elegans. , 2002, Development.

[32]  N. Nelson,et al.  The Family of Na+/Cl− Neurotransmitter Transporters , 1998, Journal of neurochemistry.

[33]  Frederick M. Ausubel,et al.  A Conserved p38 MAP Kinase Pathway in Caenorhabditis elegans Innate Immunity , 2002, Science.

[34]  T. Lamitina,et al.  Genome-wide RNAi screening identifies protein damage as a regulator of osmoprotective gene expression , 2006, Proceedings of the National Academy of Sciences.

[35]  S. Hannenhalli,et al.  Genetic and Physiological Activation of Osmosensitive Gene Expression Mimics Transcriptional Signatures of Pathogen Infection in C. elegans , 2010, PloS one.

[36]  Leo X. Liu,et al.  Addresses: 1Laboratoire de Génétique et , 2022 .

[37]  B. Beutler,et al.  Intracellular toll-like receptors. , 2010, Immunity.

[38]  A. Chisholm,et al.  Negative regulation of Caenorhabditis elegans epidermal damage responses by death-associated protein kinase , 2009, Proceedings of the National Academy of Sciences.

[39]  F. Ausubel,et al.  Models of Caenorhabditis elegans infection by bacterial and fungal pathogens. , 2008, Methods in molecular biology.

[40]  O. Zugasti,et al.  Neuroimmune regulation of antimicrobial peptide expression by a noncanonical TGF-β signaling pathway in Caenorhabditis elegans epidermis , 2009, Nature Immunology.

[41]  Kunihiro Matsumoto,et al.  Phosphorylation of the Conserved Transcription Factor ATF-7 by PMK-1 p38 MAPK Regulates Innate Immunity in Caenorhabditis elegans , 2010, PLoS genetics.

[42]  J. Ewbank.  Tackling both sides of the host-pathogen equation with Caenorhabditis elegans. , 2002, Microbes and infection.

[43]  B. Lemaître,et al.  The host defense of Drosophila melanogaster. , 2007, Annual review of immunology.

[44]  O. Zugasti,et al.  Anti-Fungal Innate Immunity in C. elegans Is Enhanced by Evolutionary Diversification of Antimicrobial Peptides , 2008, PLoS pathogens.

[45]  M. Veenhuis,et al.  ULTRASTRUCTURAL-STUDY OF ADHESION AND INITIAL-STAGES OF INFECTION OF NEMATODES BY CONIDIA OF DRECHMERIA-CONIOSPORA , 1990 .

[46]  E. Eisenberg,et al.  Caenorhabditis elegans auxilin: a J-domain protein essential for clathrin-mediated endocytosis in vivo , 2001, Nature Cell Biology.

[47]  W. Wood.  The Nematode Caenorhabditis elegans , 1988 .