title: TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages.
abstract: The activation of transcription factors is critical to ensure an effective defense against pathogens. In this study we identify a critical and complementary role of the transcription factors TFEB and TFE3 in innate immune response. By using a combination of chromatin immunoprecipitation, CRISPR-Cas9-mediated genome-editing technology, and in vivo models, we determined that TFEB and TFE3 collaborate with each other in activated macrophages and microglia to promote efficient autophagy induction, increased lysosomal biogenesis, and transcriptional upregulation of numerous proinflammatory cytokines. Furthermore, secretion of key mediators of the inflammatory response (CSF2, IL1B, IL2, and IL27), macrophage differentiation (CSF1), and macrophage infiltration and migration to sites of inflammation (CCL2) was significantly reduced in TFEB and TFE3 deficient cells. These new insights provide us with a deeper understanding of the transcriptional regulation of the innate immune response.
authors.affiliation: a Department of Molecular and Human Genetics , Baylor College of Medicine , Houston , TX , USA.|b Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital , Houston , TX , USA.
authors.forename: Nunzia
authors.initials: N
authors.lastname: Pastore
authors.affiliation: c Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda , MD , USA.
authors.forename: Owen A
authors.initials: OA
authors.lastname: Brady
authors.affiliation: c Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda , MD , USA.
authors.forename: Heba I
authors.initials: HI
authors.lastname: Diab
authors.affiliation: c Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda , MD , USA.
authors.forename: José A
authors.initials: JA
authors.lastname: Martina
authors.affiliation: c Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda , MD , USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.affiliation: a Department of Molecular and Human Genetics , Baylor College of Medicine , Houston , TX , USA.|b Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital , Houston , TX , USA.
authors.forename: Tuong
authors.initials: T
authors.lastname: Huynh
authors.affiliation: d Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health , Bethesda , MD , USA.
authors.forename: Jeong-A
authors.initials: JA
authors.lastname: Lim
authors.affiliation: d Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health , Bethesda , MD , USA.
authors.forename: Hossein
authors.initials: H
authors.lastname: Zare
authors.affiliation: d Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health , Bethesda , MD , USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Raben
authors.affiliation: a Department of Molecular and Human Genetics , Baylor College of Medicine , Houston , TX , USA.|b Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital , Houston , TX , USA.|e Telethon Institute of Genetics and Medicine (TIGEM) , Naples , Italy.|f Medical Genetics, Department of Translational Medicine, Federico II University , Naples , Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.affiliation: c Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda , MD , USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Puertollano
mesh_terms: D000818:Animals; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism; D000067996:RAW 264.7 Cells
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C069203:TFE3 protein, human; C064972:TFEB protein, human
keywords: Tfe3; Tfeb; autophagy; immune response; macrophages