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Epigenetic regulation of the expression of Il12 and Il23 and autoimmune inflammation by the deubiquitinase Trabid

Nature Immunology volume 17, pages 259–268 (2016)Cite this article

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Abstract

The proinflammatory cytokines interleukin 12 (IL-12) and IL-23 connect innate responses and adaptive immune responses and are also involved in autoimmune and inflammatory diseases. Here we describe an epigenetic mechanism for regulation of the genes encoding IL-12 (Il12a and Il12b; collectively called 'Il12' here) and IL-23 (Il23a and Il12b; collectively called 'Il23' here) involving the deubiquitinase Trabid. Deletion of Zranb1 (which encodes Trabid) in dendritic cells inhibited induction of the expression of Il12 and Il23 by Toll-like receptors (TLRs), which impaired the differentiation of inflammatory T cells and protected mice from autoimmune inflammation. Trabid facilitated TLR-induced histone modifications at the promoters of Il12 and Il23, which involved deubiqutination and stabilization of the histone demethylase Jmjd2d. Our findings highlight an epigenetic mechanism for the regulation of Il12 and Il23 and establish Trabid as an innate immunological regulator of inflammatory T cell responses.

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Figure 1: Zranb1-deficient mice are resistant to CNS inflammation.
Figure 2: Trabid is dispensable in T cells but crucial in DCs for the induction of EAE.
Figure 3: Trabid is required for induction IL-12 and IL-23 (proteins are referred in this case) in cells of the innate immune system.
Figure 4: Trabid is dispensable for TLR-stimulated signaling but is important for the recruitment of c-Rel to Il12 promoters.
Figure 5: Trabid functions as a DUB to facilitate histone demethylation at the Il12b promoter and induction of Il12 expression.
Figure 6: Trabid regulates the stability and function of Jmjd2d.

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Acknowledgements

We thank M. Bienz (Medical Research Council, UK) for the plasmid pHM6-HA-Trabid; the EUCOMM Consortium for mice in which Zranb1 was targeted; and personnel from M.D. Anderson Cancer Center resources (flow cytometry, DNA analysis and animal facilities) supported by the National Cancer Institute of the US National Institutes of Health (P30CA016672). Supported by the US National Institutes of Health (AI064639, AI057555 and AI104519), the Center for Inflammation and Cancer at M.D. Anderson Cancer Center, the National Natural Science Foundation of China (81572651), the Thousand Young Talents Plan of China, and the Zhejiang University Special Fund for Fundamental Research.

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Author notes

  1. Jin Jin and Xiaoping Xie: These authors contributed equally to this work.

Authors and Affiliations

  1. Life Sciences Institute, Zhejiang University, Hangzhou, China

    Jin Jin

  2. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Jin Jin, Xiaoping Xie, Yichuan Xiao, Hongbo Hu, Qiang Zou, Xuhong Cheng & Shao-Cong Sun

  3. Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yichuan Xiao

  4. State Key Laboratory of Biotherapy, West China Hospital, Si-Chuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China

    Hongbo Hu

  5. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA

    Shao-Cong Sun

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Contributions

J.J. designed and performed the research, prepared the figures and wrote the manuscript; X.X. made major contributions to the research and prepared some of the figures; Y.X., H.H., Q.Z., and X.C. contributed to experiments; and S.-C.S. supervised the work and wrote the manuscript.

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Correspondence to Shao-Cong Sun.

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Integrated supplementary information

Supplementary Figure 1 Zranb1 gene targeting.

(a) Schematic picture of Zranb1 gene targeting using an FRT-LoxP vector, showing the first 6 exons of Zranb1 gene (exons 7-9 are not shown). Targeted mice were crossed with FRT deleter (Rosa26-FLPe) mice to generate Zranb1-floxed mice, which were further crossed with different Cre mice to generate germline KO (CMV-Cre), T-cKO (Cd4-Cre), or DC-cKO (Cd11c-Cre) mice. (b) Genotyping PCR analysis of germline Zranb1 wild-type (WT), KO (KO), and heterozygous (Het) mice using P1/P2 primer pair for wild-type allele and P1/P4 primer pair for KO allele. (c,d) Genotyping PCR of T cell-conditional Zranb1 wild-type (WT, Zranb1+/+Cd4-Cre), T-cKO (Zranb1f/fCd4-Cre), and heterozygous (T-cKO Het, Zranb1+/fCd4-Cre) mice (c) or DC-conditional Zranb1 wild-type (WT, Zranb1+/+Cd11c-Cre), DC-cKO (Zranb1f/fCd11c-Cre), and heterozygous (DC-cKO Het, Zranb1+/fCd11c-Cre) mice (d) using P3/P4 primer pair to amplify WT and floxed alleles and Cre-specific primers for the Cd4-Cre and Cd11c-Cre DNA. (e) RT-PCR was performed to measure the Zranb1 mRNA level in the indicated cell types.

Supplementary Figure 2 Development of cells of the immune system in mice with germline deletion of Zranb1.

(a) Flow cytometry analysis of the percentage (numbers in quadrants) of CD4+CD8+ double-positive (DP), CD4+ and CD8+ single-positive (SP) thymocytes in the thymus (Thy) and B220+ B cells (B) and CD4+ and CD8+ T cells in the spleen (Spl) of wild-type (WT) and KO mice. (b) Flow cytometry analysis of naïve (N, CD62hiCD44lo) and memory (M, CD62loCD44hii) CD4+ T cells and naïve (N), central memory (CM, CD62LhiCD44hi), and effector memory (EM, CD62loCD44hi) CD8+ T cells in the spleen of wild-type and KO mice. (c) Flow cytometry analysis of the Foxp3+ Treg cells in the spleen and thymus of wild-type (WT) or KO mice. (d) Flow cytometry analysis of conventional DC (cDC, CD11c+CD11bhiB220−) and plasmacytoid DC (pDC, CD11c+CD11b−B220+) percentage in total CD11c-positive cells of Bone marrow (BM) and Spleen (Spl). Data in all panels are presented as a representative FACS plots (left) and mean ± SEM values based on multiple samples (right). Similar results were obtained in three independent experiments. *P<0.05.

Supplementary Figure 3 Trabid is dispensable in T cells for T cell activation and EAE induction.

Age- and sex-matched wild-type (WT) and T-cKO mice were subjected to MOG35-55-induced EAE. (a) Flow cytometry analysis of the CD45+ immune cells (CD4+ and CD8+ T cells and CD11b+ monocytes) infiltrated into the CNS (brain and spinal cord) (n = 3, day 14 post-immunization), presented as a representative plot (left) and summary graph (right). (b) Flow cytometry analysis of the IFN-γ-producing TH1 and IL-17A-producing TH17 cells in the CNS (percent of CD4+CD45+ cells) and draining lymph nodes (percent of CD4+ T cells) (n = 3, day 14 post-immunization). Data are presented as a representative plot (left, CNS only) and summary graph of absolute cell numbers (right). (c) ELISA analysis of the indicated cytokines in the supernatants of cultures of splenocytes isolated from WT and T-cKO EAE mice (day 14 after immunization) and restimulated in vitro with MOG peptide (20 μg/ml for 48 h). (d) Flow cytometry analysis of the frequency of TH1, TH17, and TREG cells in wild-type and T-cKO naive CD4+ T cells, stimulated for 4 days with plate-bound anti-CD3 and anti-CD28 antibodies under TH0, TH1, TH17, or TREG conditions. (e) Flow cytometry analysis of cell proliferation, based on CFSE dilution, of naïve T cells stimulated with plate-bound anti-CD3 (5 μg/mL) and anti-CD28 (1 μg/mL) for 48 h. (f) ELISA of IFN-γ and IL-2 using supernatants of the cell cultures described in e. Data are representative of three independent experiments. Error bars are mean ± SEM values.

Supplementary Figure 4 Effect of Trabid deficiency on the function of DCs in regulating T cell differentiation.

(a,b) Flow cytometry analysis of Foxp3+ TREG cells (a) or IFN-γ+ TH1 and IL-17+ TH17 cells (b) in wild-type naïve CD4+ T cells stimulated for 4 days with plate-bound anti-CD3 and anti-CD28 plus supernatant of LPS-activated wild-type (WT) or DC-cKO BMDCs (LPS-DC) in the absence (–) or presence (+) of the indicated cytokines.

Supplementary Figure 5 Trabid regulates LPS-stimulated c-Rel recruitment and histone modifications at the promoters of Il12a and Il12b.

(a) ChIP assays of c-Rel recruitment to the promoter of the indicated genes using wild-type (WT) and DC-cKO BMDCs that were either unstimulated (0 h) or stimulated for 6 h with LPS. Data are presented as percentage of the total input DNA, as determined by QPCR assays. (b) Luciferase assays using HEK293 cells transfected with an Il12b-luciferase reporter plasmid in the presence (+) or absence (–) of an empty vector (Vector) or expression vectors encoding c-Rel, Trabid, or a catalytically inactive Trabid mutant, C443 (Mut Trabid). Luciferase activity is presented as fold based on empty vector. (c) ChIP analyses of H3K9 dimethylation (H3K9me2) and trimethylation (H3K9me3) in the Il12a promoter using wild-type or DC-cKO BMDCs that were untreated (NT) or stimulated with LPS for 6 h. The Y axis is percentage (%) of total H3. Data are presented as mean ± SEM values and representative of at least three independent experiments. Statistical analyses represent variations in technical replicates *P < 0.05; **P < 0.01.

Supplementary Figure 6 Trabid deficiency suppresses the recruitment of Pol II complex components to the Il12b promoter.

ChIP analysis of the recruitment of Pol II, Pol II pS5, TFIIB, and TFIID to the indicated promoters in wild-type (WT) or DC-cKO BMDCs. The Y axis is percentage (%) of the DNA bound to the specific factors based on total input DNA. Data are presented as mean ± SEM values and representative of at least three independent experiments. Statistical analyses represent variations in technical replicates. *P < 0.05; **P < 0.01.

Supplementary Figure 7 Jmjd2d is regulated by Trabid and mediates induction of Il12 genes.

(a,b) ChIP analysis of the binding of indicated Jmjd2 family members to different regions of Il12b locus in wild-type (WT) and DC-cKO BMDCs (a) or wild-type and Rel-KO BMDCs (b) that were either not treated (NT) or stimulated with LPS for 6 h. (c) Immunoblotting analysis of Jmjd2d in wild-type BMDCs transduced with pGIPZ lentiviral vectors encoding a non-silencing control shRNA (C) or two different Kdm4d-specific shRNAs. The cells were stimulated with LPS for 6 h to induce the level of Jmjd2d. (d) qRT-PCR analysis of the indicated genes in LPS-stimulated BMDCs described in c. Data are presented as fold relative to the Actb mRNA level. (e) Immunoblotting analysis of HA-tagged Trabid (or Trabid C443A) and FLAG-tagged Jmjd2d in anti-FLAG (Jmjd2d) immunoprecipitates (top two panels) or lysates (lower panels) of HEK293 cells transfected with the indicated plasmids. (f,g) Immunoblotting analysis of Jmjd2d (f) and qRT-PCR analysis of the indicated genes in DC-cKO BMDCs reconstituted with pCLXSN(GFP) (Vec) or pCLXSN(GFP)-HA-Jmjd2d (Jmjd2d). Data are presented as mean ± SEM values and representative of at least three independent experiments. *P < 0.05; **P<0.01.

Supplementary Figure 8 A model of Trabid function in TLR-mediated induction of Il12b.

LPS induces the expression of the Jmjd2d gene (Kdm4d) via an unknown signaling pathway. Jmjd2d mediates removal of H3K9me2 and H3K9me3 from the Il12b promoter, thereby promoting c-Rel binding to the κB element and induction of Il12b expression. The fate of Jmjd2d in TLR-stimulated DCs is tightly controlled by ubiquitination. An unknown E3 ubiquitin ligase mediates Jmjd2d ubiquitination and degradation, whereas Trabid deubiquitinates Jmjd2d to prevent its degradation. Trabid deficiency causes elevated ubiquitination and degradation of Jmjd2d and, thus, reduces the level of Il12b induction. Similar mechanisms may apply to the induction of Il12a and Il23a genes.

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Jin, J., Xie, X., Xiao, Y. et al. Epigenetic regulation of the expression of Il12 and Il23 and autoimmune inflammation by the deubiquitinase Trabid. Nat Immunol 17, 259–268 (2016). https://doi.org/10.1038/ni.3347

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