MicroRNA-21 regulates T-cell apoptosis by directly targeting the tumor suppressor gene Tipe2

Q Ruan,Y H Chen,X Wan,T Fan,J Qi,S Wang,H Sun,D Johnson,P Wang,M Wei,T Wang,W Shi

doi:10.1038/cddis.2014.47

Abstract

MicroRNAs (MiRs) are short noncoding RNAs that can regulate gene expression. It has been reported that miR-21 suppresses apoptosis in activated T cells, but the molecular mechanism remains undefined. Tumor suppressor Tipe2 (or tumor necrosis factor-α-induced protein 8 (TNFAIP8)-like 2 (TNFAIP8L2)) is a newly identified anti-inflammatory protein of the TNFAIP8 family that is essential for maintaining immune homeostasis. We report here that miR-21 is a direct target of nuclear factor-κB and could regulate Tipe2 expression in a Tipe2 coding region-dependent manner. In activated T cells and macrophages, Tipe2 expression was markedly downregulated, whereas miR-21 expression was upregulated. Importantly, Tipe2-deficient T cells were significantly less sensitive to apoptosis. Conversely, overexpression of Tipe2 in EL-4 T cells increased their susceptibility to activation-induced apoptosis. Therefore, Tipe2 provides a molecular bridge between miR-21 and cell apoptosis; miR-21 suppresses apoptosis in activated T cells at least in part through directly targeting tumor suppressor gene Tipe2.

Highlights

(miRNAs) in the regulation of cell functions has become more and more apparent
To test the expression of Tipe[2] protein in T cells, western blot analysis were performed for naive CD4 þ T cells either untreated or treated with anti-CD3 plus anti-CD28 for 5 h
Consistent with published data that miR-21 is a potential target of nuclear factor-kB (NF-kB),[39,40,41] we found that miR-21 expression was induced by anti-CD3 plus anti-CD28 treatment in CD4 þ T cells (Figure 2a) and LPS treatment in macrophages (Figure 2b), but was partially blocked by the NF-kB inhibitor Bay 11-7082 (Figures 2a and b)

Summary

Introduction

(miRNAs) in the regulation of cell functions has become more and more apparent These small but potent regulators have important roles in a range of processes, including hematopoietic cell development, immunity, and carcinogenesis.[1,2,3,4,5,6,7] MiRNAs are small (B22 nucleotide), noncoding RNAs that can pair with complementary sequences within mRNA molecules. Apoptosis of mature T lymphocytes is regulated by extensive networks of signal-transduction pathways. This ensures controlled activation and expansion of cells during immune responses and apoptotic deletion of lymphoid cells that are no longer needed at the end of immune responses.[30] T-cell apoptosis occurs in at least two major forms: antigen-driven and lymphokine withdrawal-induced. Tipe[2] overexpression induced cell death and significantly inhibited Ras-induced tumorigenesis in mice.[38]

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Conclusion