miR-17-92 cluster targets phosphatase and tensin homology and Ikaros Family Zinc Finger 4 to promote TH17-mediated inflammation.

Journal Article (Journal Article)

The miR-17-92 cluster regulates a broad spectrum of biological processes of T cell immunity. This cluster was found to facilitate T cell proliferation, enhance antitumor activities and promote T cell-dependent antibody responses. However, little is known about the role of this miRNA cluster in the development of autoimmune diseases. Multiple sclerosis is a neuro-destructive autoimmune disease caused by the pathogenicity of TH17 cells, whose differentiation is tightly controlled by a variety of transcriptional and post-transcriptional regulators. Our study unveils the critical role of miR-17-92 in TH17 differentiation: T cell-specific miR-17-92 deficiency reduced TH17 differentiation and ameliorated experimental autoimmune encephalomyelitis (EAE) symptoms. We demonstrated that miR-17 and miR-19b are the two miRNAs in this cluster responsible for promoting TH17 responses. MiR-19b represses the expression of Phosphatase and Tensin Homology (PTEN), thereby augmenting the PI3K-AKT-mTOR axis essential for proper TH17 differentiation. Meanwhile, miR-17 enhances TH17 polarization by inhibiting a novel target, Ikaros Family Zinc Finger 4 (IKZF4). By establishing the miR-17-92 cluster as a key driver of TH17 responses, our data identify this miRNA cluster as a potential therapeutic target for the clinical intervention of multiple sclerosis.

Full Text

Duke Authors

Cited Authors

  • Liu, S-Q; Jiang, S; Li, C; Zhang, B; Li, Q-J

Published Date

  • May 2, 2014

Published In

Volume / Issue

  • 289 / 18

Start / End Page

  • 12446 - 12456

PubMed ID

  • 24644282

Pubmed Central ID

  • PMC4007439

Electronic International Standard Serial Number (EISSN)

  • 1083-351X

Digital Object Identifier (DOI)

  • 10.1074/jbc.M114.550723


  • eng

Conference Location

  • United States