期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 18, 页码 12446-12456出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.550723
关键词
Autoimmunity; Cell Differentiation; Inflammation; MicroRNA; Pten; T Cell; IKZF4; Th17; miR-17-92
资金
- NIAID, National Institutes of Health [RAI091878A, RAI091878B]
Background: miRNA is a key component of post-transcriptional network governing the fate of T cells. Results: By targeting PTEN and IKZF4, miR-17-92 cluster promotes T(H)17 differentiation and T(H)17-related inflammation. Conclusion: miR-19b and miR-17 within the cluster additively promote T(H)17 responses through distinct regulatory networks. Significance: Our study provides novel regulatory mechanisms and potential therapeutic candidates against autoimmunity. 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 T(H)17 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 T(H)17 differentiation: T cell-specific miR-17-92 deficiency reduced T(H)17 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 T(H)17 responses. MiR-19b represses the expression of Phosphatase and Tensin Homology (PTEN), thereby augmenting the PI3K-AKT-mTOR axis essential for proper T(H)17 differentiation. Meanwhile, miR-17 enhances T(H)17 polarization by inhibiting a novel target, Ikaros Family Zinc Finger 4 (IKZF4). By establishing the miR-17-92 cluster as a key driver of T(H)17 responses, our data identify this miRNA cluster as a potential therapeutic target for the clinical intervention of multiple sclerosis.
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