RNA-Binding Protein ZFP36L2 Downregulates Helios Expression and Suppresses the Function of Regulatory T Cells
The zinc finger protein 36-like 2, ZFP36L2, is a member of a small family of RNA-binding proteins composed by ZFP36 (also known as tristetraprolin, TTP), ZFP36L1 and ZFP36L2 in humans, with corresponding murine orthologs. These proteins bind to adenine uridine-rich element (ARE) in the 3′untranslate...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.01291/full |
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| author | Sohei Makita Hiroaki Takatori Hiroaki Takatori Arifumi Iwata Shigeru Tanaka Shunsuke Furuta Kei Ikeda Akira Suto Kotaro Suzuki Silvia B. V. Ramos Hiroshi Nakajima |
| author_facet | Sohei Makita Hiroaki Takatori Hiroaki Takatori Arifumi Iwata Shigeru Tanaka Shunsuke Furuta Kei Ikeda Akira Suto Kotaro Suzuki Silvia B. V. Ramos Hiroshi Nakajima |
| author_sort | Sohei Makita |
| collection | DOAJ |
| description | The zinc finger protein 36-like 2, ZFP36L2, is a member of a small family of RNA-binding proteins composed by ZFP36 (also known as tristetraprolin, TTP), ZFP36L1 and ZFP36L2 in humans, with corresponding murine orthologs. These proteins bind to adenine uridine-rich element (ARE) in the 3′untranslated region of target messenger RNA and stimulate target degradation. ZFP36 functions as an anti-inflammatory modulator in murine models of inflammatory diseases by down-regulating the production of inflammatory cytokines such as tumor necrosis factor-α. However, how ZFP36L1 and ZFP36L2 alter the function of CD4+ T cells is not completely understood. We addressed this issue by searching for the target genes of ZFP36L2 by comprehensive transcriptome analysis. We observed that ZFP36L2 is highly expressed in naïve CD4+ T cells; however, when CD4+ T cells are stimulated through their T cell receptors, ZFP36L2 expression is rapidly reduced in both humans and mice. Among CD4+ T cell populations, the expression levels of ZFP36L2 in regulatory T cells (Tregs) were significantly lower than those in naïve or effector CD4+ T cells. RNA-sequence analysis revealed that the forced expression of ZFP36L2 decreased Ikzf2 (encoding Helios) expression in Foxp3+ Tregs and inhibited the ability of induced Tregs (iTregs). ZFP36L2 directly bound to and destabilized the 3′untranslated region of Ikzf2 mRNA, which contains AU-rich elements. These results indicate that ZFP36L2 reduces the expression of Ikzf2 and suppresses iTreg function, raising the interesting possibility that the inhibition of ZFP36L2 in iTregs could be a therapeutic strategy for autoimmune diseases. |
| first_indexed | 2024-12-21T16:02:01Z |
| format | Article |
| id | doaj.art-1e8cda9158eb45878aa502afd3625bf0 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-21T16:02:01Z |
| publishDate | 2020-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-1e8cda9158eb45878aa502afd3625bf02022-12-21T18:57:58ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-06-011110.3389/fimmu.2020.01291518392RNA-Binding Protein ZFP36L2 Downregulates Helios Expression and Suppresses the Function of Regulatory T CellsSohei Makita0Hiroaki Takatori1Hiroaki Takatori2Arifumi Iwata3Shigeru Tanaka4Shunsuke Furuta5Kei Ikeda6Akira Suto7Kotaro Suzuki8Silvia B. V. Ramos9Hiroshi Nakajima10Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, JapanDepartment of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, JapanDepartment of Rheumatology, Hamamatsu Medical Center, Shizuoka, JapanDepartment of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, JapanDepartment of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, JapanDepartment of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, JapanDepartment of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, JapanDepartment of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, JapanDepartment of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, JapanDepartment of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDepartment of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, JapanThe zinc finger protein 36-like 2, ZFP36L2, is a member of a small family of RNA-binding proteins composed by ZFP36 (also known as tristetraprolin, TTP), ZFP36L1 and ZFP36L2 in humans, with corresponding murine orthologs. These proteins bind to adenine uridine-rich element (ARE) in the 3′untranslated region of target messenger RNA and stimulate target degradation. ZFP36 functions as an anti-inflammatory modulator in murine models of inflammatory diseases by down-regulating the production of inflammatory cytokines such as tumor necrosis factor-α. However, how ZFP36L1 and ZFP36L2 alter the function of CD4+ T cells is not completely understood. We addressed this issue by searching for the target genes of ZFP36L2 by comprehensive transcriptome analysis. We observed that ZFP36L2 is highly expressed in naïve CD4+ T cells; however, when CD4+ T cells are stimulated through their T cell receptors, ZFP36L2 expression is rapidly reduced in both humans and mice. Among CD4+ T cell populations, the expression levels of ZFP36L2 in regulatory T cells (Tregs) were significantly lower than those in naïve or effector CD4+ T cells. RNA-sequence analysis revealed that the forced expression of ZFP36L2 decreased Ikzf2 (encoding Helios) expression in Foxp3+ Tregs and inhibited the ability of induced Tregs (iTregs). ZFP36L2 directly bound to and destabilized the 3′untranslated region of Ikzf2 mRNA, which contains AU-rich elements. These results indicate that ZFP36L2 reduces the expression of Ikzf2 and suppresses iTreg function, raising the interesting possibility that the inhibition of ZFP36L2 in iTregs could be a therapeutic strategy for autoimmune diseases.https://www.frontiersin.org/article/10.3389/fimmu.2020.01291/fullZFP36L2Heliosregulatory T cellsAU-rich element3′untranslated region |
| spellingShingle | Sohei Makita Hiroaki Takatori Hiroaki Takatori Arifumi Iwata Shigeru Tanaka Shunsuke Furuta Kei Ikeda Akira Suto Kotaro Suzuki Silvia B. V. Ramos Hiroshi Nakajima RNA-Binding Protein ZFP36L2 Downregulates Helios Expression and Suppresses the Function of Regulatory T Cells Frontiers in Immunology ZFP36L2 Helios regulatory T cells AU-rich element 3′untranslated region |
| title | RNA-Binding Protein ZFP36L2 Downregulates Helios Expression and Suppresses the Function of Regulatory T Cells |
| title_full | RNA-Binding Protein ZFP36L2 Downregulates Helios Expression and Suppresses the Function of Regulatory T Cells |
| title_fullStr | RNA-Binding Protein ZFP36L2 Downregulates Helios Expression and Suppresses the Function of Regulatory T Cells |
| title_full_unstemmed | RNA-Binding Protein ZFP36L2 Downregulates Helios Expression and Suppresses the Function of Regulatory T Cells |
| title_short | RNA-Binding Protein ZFP36L2 Downregulates Helios Expression and Suppresses the Function of Regulatory T Cells |
| title_sort | rna binding protein zfp36l2 downregulates helios expression and suppresses the function of regulatory t cells |
| topic | ZFP36L2 Helios regulatory T cells AU-rich element 3′untranslated region |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.01291/full |
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