TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages

• Published in: Autophagy Vol. 12; no. 8; pp. 1240 - 1258
• Main Authors: Pastore, Nunzia, Brady, Owen A., Diab, Heba I., Martina, José A., Sun, Lu, Huynh, Tuong, Lim, Jeong-A, Zare, Hossein, Raben, Nina, Ballabio, Andrea, Puertollano, Rosa
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02.08.2016
• Subjects: Animals; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Basic Research Paper; Cell Nucleus - metabolism; Cytosol - metabolism; Female; Gene Expression Regulation; HEK293 Cells; Humans; immune response; Immunity, Innate; Inflammation; Macrophage Activation; macrophages; Macrophages - metabolism; Male; Mice; Microglia - metabolism; RAW 264.7 Cells; Tfe3; Tfeb; Tfeb; macrophages; autophagy; immune response; Tfe3
• ISSN: 1554-8627; 1554-8635
• DOI: 10.1080/15548627.2016.1179405

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.