title: An Evolutionarily Conserved PLC-PKD-TFEB Pathway for Host Defense.
abstract: The mechanisms that tightly control the transcription of host defense genes have not been fully elucidated. We previously identified TFEB as a transcription factor important for host defense, but the mechanisms that regulate TFEB during infection remained unknown. Here, we used C. elegans to discover a pathway that activates TFEB during infection. Gene dkf-1, which encodes a homolog of protein kinase D (PKD), was required for TFEB activation in nematodes infected with Staphylococcus aureus. Conversely, pharmacological activation of PKD was sufficient to activate TFEB. Furthermore, phospholipase C (PLC) gene plc-1 was also required for TFEB activation, downstream of Gαq homolog egl-30 and upstream of dkf-1. Using reverse and chemical genetics, we discovered a similar PLC-PKD-TFEB axis in Salmonella-infected mouse macrophages. In addition, PKCα was required in macrophages. These observations reveal a previously unknown host defense signaling pathway, which has been conserved across one billion years of evolution.
authors.affiliation: Laboratory of Comparative Immunology, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Mehran
authors.initials: M
authors.lastname: Najibi
authors.affiliation: Laboratory of Comparative Immunology, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Sid Ahmed
authors.initials: SA
authors.lastname: Labed
authors.affiliation: Laboratory of Comparative Immunology, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Orane
authors.initials: O
authors.lastname: Visvikis
authors.affiliation: Laboratory of Comparative Immunology, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA. Electronic address: jirazoqui@mgh.harvard.edu.
authors.forename: Javier Elbio
authors.initials: JE
authors.lastname: Irazoqui
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000382:microbiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D004789:Enzyme Activation; D019143:Evolution, Molecular; D054884:Host-Pathogen Interactions / Q000276:immunology*; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D050296:Microbial Viability; D011493:Protein Kinase C / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000378:metabolism; D000067996:RAW 264.7 Cells; D019779:Salmonella enterica / Q000502:physiology; D015398:Signal Transduction; D013203:Staphylococcal Infections / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D013211:Staphylococcus aureus / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D029742:Caenorhabditis elegans Proteins; C089212:protein kinase D; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D010738:Type C Phospholipases