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

被引:232
作者
Pastore, Nunzia [1 ,2 ]
Brady, Owen A. [3 ]
Diab, Heba I. [3 ]
Martina, Jose A. [3 ]
Sun, Lu [3 ]
Tuong Huynh [1 ,2 ]
Lim, Jeong-A [4 ]
Zare, Hossein [4 ]
Raben, Nina [4 ]
Ballabio, Andrea [1 ,2 ,5 ,6 ]
Puertollano, Rosa [3 ]
机构
[1] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
[2] Texas Children Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX USA
[3] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA
[4] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA
[5] Telethon Inst Genet & Med TIGEM, Via Campi Flegrei 34, I-80078 Naples, Italy
[6] Univ Naples Federico II, Dept Translat Med, Med Genet, Naples, Italy
基金
美国国家卫生研究院;
关键词
autophagy; immune response; macrophages; Tfe3; Tfeb; TRANSCRIPTION FACTOR; LYSOSOMAL BIOGENESIS; BACTERIAL PATHOGENS; PROBE LEVEL; IN-VIVO; AUTOPHAGY; MTORC1; PATHWAYS; FAMILY; CELLS;
D O I
10.1080/15548627.2016.1179405
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:1240 / 1258
页数:19
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