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K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8+ T cell activation

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Abstract

The key molecular mechanisms that control signaling via T cell antigen receptors (TCRs) remain to be fully elucidated. Here we found that Nrdp1, a ring finger–type E3 ligase, mediated Lys33 (K33)-linked polyubiquitination of the signaling kinase Zap70 and promoted the dephosphorylation of Zap70 by the acidic phosphatase–like proteins Sts1 and Sts2 and thereby terminated early TCR signaling in CD8+ T cells. Nrdp1 deficiency significantly promoted the activation of naive CD8+ T cells but not that of naive CD4+ T cells after engagement of the TCR. Nrdp1 interacted with Zap70 and with Sts1 and Sts2 and connected K33 linkage of Zap70 to Sts1- and Sts2-mediated dephosphorylation. Our study suggests that Nrdp1 terminates early TCR signaling by inactivating Zap70 and provides new mechanistic insights into the non-proteolytic regulation of TCR signaling by E3 ligases.

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Figure 1: Nrdp1 deficiency promotes the proliferation and activation of CD8+ T cells.
Figure 2: Nrdp1 deficiency promotes the antigen-specific activity of CD8+ T cells.
Figure 3: Nrdp1 deficiency accelerates EAE remission by polarizing IFN-γ production.
Figure 4: The E3 ligase activity of Nrdp1 is required for the suppression of CD8+ T cell activation by Nrdp1.
Figure 5: Nrdp1 deficiency exaggerates TCR signaling during CD8+ T cell activation.
Figure 6: Nrdp1 interacts with Zap70, Sts1 and Sts2 via its carboxy-terminal domain.
Figure 7: Nrdp1 polyubiquitinates Zap70 at Lys578.
Figure 8: Nrdp1 inactivates Zap70 via Sts1- and Sts2-mediated dephosphorylation.

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  • 22 November 2019

    Editor's Note: It has been reported that the flow cytometric profile in Figure 2a, lower right panel, is a duplicate of the profile in Figure 2b, upper left panel. We can confirm that this is the case, and that the error was inadvertently introduced during the production process. We are now checking the remaining figures and will issue a correction when this has been completed. We would like to apologize for any inconvenience to our readers and the authors.

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Acknowledgements

We thank H. Shen (University of Pennsylvania School of Medicine) for virulent recombinant L. monocytogenes (LM-OVA) and attenuated recombinant L. monocytogenesactA-LM-OVA); H. Shen, X. Zhu and Z. Li for technical assistance; L. Lu for discussions; and Q. Guo for assistance with confocal microscopy. Supported by the National Key Basic Research Program of China (2010CB911903 and 2013CB530500), the National Natural Science Foundation of China (81222039, 81172851, 81471566, 31170863, 81123006 and 31390431), the National Excellent Doctoral Dissertation of China (200775) and the Shanghai Committee of Science and Technology (11QH1402900).

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Authors

Contributions

M.Y., T.C., X.L., Z.Y., S.T. and C.W. did the main experiments and analyzed data; M.Y., Y.G., Y.L. and S.X. performed flow cytometry assays; W.L. and X.Z. assisted with the liquid chromatography–mass spectrometry; J.W. contributed materials; and X.C. and T.C. designed and supervised the experiments and wrote the manuscript.

Corresponding authors

Correspondence to Taoyong Chen or Xuetao Cao.

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The authors declare no competing financial interests.

Additional information

Editor's Note: It has been reported that the flow cytometric profile in Figure 2a, lower right panel, is a duplicate of the profile in Figure 2b, upper left panel. We can confirm that this is the case, and that the error was inadvertently introduced during the production process. We are now checking the remaining figures and will issue a correction when this has been completed. We would like to apologize for any inconvenience to our readers and the authors.

Integrated supplementary information

Supplementary Figure 1 Establishment and identification of Nrdp1–/– mice.

(a) Gene trap strategy used to construct Nrdp1–/– mice. (b) RT-PCR assays of mice tail. For results reading, “0” indicates for candidate of Nrdp1–/–, “1” for candidate of Nrdp1+/–, and “S” for suspicion existed that needs a second round of genotyping. M, DNA marker; C, positive control (RAW264.7 cells); N, negative control without template. (c) Whole cell lysates of indicated tissues or cells were examined for Nrdp1 expression by immunoblot.

Supplementary Figure 2 Nrdp1 deficiency does not affect the distribution of cells of the immune system.

Single-cell suspensions of indicated tissues were stained with indicated fluorescent markers for mature T cells (a), double negative (DN, gated on CD4 and CD8 negative T cells) thymocytes (b), Treg cells (CD4+FoxP3+; c), B cells (B220+CD5+; d), dendritic cells (CD11c+Iab+; e), myeloid-derived suppressor cells (Gr1+Ly6c+; f) and NK cells (DX5+; g). aLN, axillary lymph nodes; mLN, mesenteric lymph nodes. One representative experiment of three is shown.

Supplementary Figure 3 Nrdp1 is ‘preferentially’ expressed in naive CD8+ T cells.

(a-e) Q-PCR assays of Nrdp1 mRNA in tissues (a), immune cells (b), differential populations of CD4+ or CD8+ T cells (c), in vitro polarized CD4+ T cells (d) and activated CD4+ or CD8+ T cells (e). In (d), CD4+CD62+ T cells (TH0) were cultured for 3 days with 20 ng/ml IL-2, 20 ng/ml IL-12 and 10 μg/ml anti-IL-4 (for TH1), 20 ng/ml IL-2, 100 ng/ml IL-4, 10 μg/ml anti-IL-12 and 10 μg/ml anti-IFN-γ (for TH2), 10 ng/ml TGF-β, 100 ng/ml IL-6, 10 μg/ml anti-IL-4 and 10 μg/ml anti-IFN-γ (for TH17), or 10 ng/ml TGF-β and 10 μg/ml anti-IFN-γ (for Treg). In (e), naïve CD4+ or CD8+ T cells were treated with 5 μg/ml pre-coated anti-CD3 antibody and 1 μg/ml soluble CD28 antibody as indicated. Results are presented as mean ± SD of triplicate samples. (f) Cells in (e; treated for 48h) were examined for Nrdp1 expression by immunoblot. One representative experiment of three is shown. (g) Predicted transcription factor binding sites in promoter region of Nrdp1. The transcription start site (TSS) of Nrdp1 in mouse DNA was determined by 5’ RACE method. The conserved sequences for transcription factor binding were predicted with the assistance of Proscan and TFMATRIX software.

Supplementary Figure 4 Nrdp1 deficiency significantly promotes the expression of cell surface markers and CD8+ T cell–related functional genes in naive CD8+ T cells.

Naïve Nrdp1+/+ or Nrdp1–/– CD8+ T cells were treated with anti-CD3 plus anti-CD28 antibodies for 48h or 72h (for flow cytometry assays) or for 4h or 8h (for microarray or Q-PCR assays). (a, b) The expression of indicated markers was analyzed by flow cytometry. Representative results are shown (a), and the mean fluorescence intensity (MFI) of indicated markers is summarized and presented as mean ± SD of triplicate samples (b, ANOVA). (c) Total RNAs were extracted and subjected to microarray expression analysis using a high-density oligonucleotide array (Affymetrix GeneChip array). The heat map representation of the top 45 genes discovered in DNA microarray assays is shown. (d-g) Cells in (c) were examined for selected genes by Q-PCR assays. Results were presented as mean ± SD of triplicate samples (ANOVA). One representative experiment of three is shown. ns, not significant; *, P < 0.01; **, P < 0.001.

Supplementary Figure 5 Effects of Nrdp1 deficiency on the infiltration of cells of the immune system and demyelination during the induction of active EAE.

On day 16 (a) or day 20 (b), brain tissues were examined by H&E staining (a) and LFB staining (b), respectively. The green-boxed regions were manually magnified and shown in lower panels. Green arrows indicate for the typical pathogenesis sites. Bars = 100 μm.

Supplementary Figure 6 MS assays of Nrdp1-interacting proteins and the ubiquitin-modification sites in Zap70.

(a, b) Whole cell lysates derived from 1 x 109 CD8+ T cells (a, b) or splenocytes (a) without anti-CD3 plus anti-CD28 treatments were immunoprecipitated with anti-Nrdp1 antibody or IgG control. The immune complexes were separated on 1D SDS-PAGE (a) or 2D SDS-PAGE gels (b). After silver staining, the differential bands or dots were analyzed by MS. Asterisks and circles indicated for the differential bands or dots of Zap70, Sts1, Sts2, TCRα or TCRβ. (c) 293T cells were transfected with Nrdp1-Flag and Zap70-Myc for 48h. Then whole cell lysates were immunoprecipitated (IP) with anti-Flag or anti-Myc agaroses. Representative images after silver staining were shown. Indicated regions after Zap70 IP were subjected to MS assays of Ub-modification sites. The identified potential Ub-modified residues (underlined) were shown at the right side. (d-f) Alignment of Zap70 proteins from indicated species.

Supplementary Figure 7 Effects of Nrdp1 deficiency on dynamics of CD3ζ and CD28.

(a-d) Naïve CD8+ T cells derived from Nrdp1+/+ or Nrdp1−/− spleens were treated with anti-CD3 plus anti-CD28 for 5 or 10 min (for surface marker expression, a and b) or for 4h (for total marker expression, c and d). The expression of indicated markers was evaluated with flow cytometry (upper two rows), and mean fluorescence intensity (MFI) of indicated markers was presented as mean ± SD of triplicate samples (the third row, ANOVA). ns, not significant. One representative experiment of three is shown.

Supplementary Figure 8 Statistical analysis of immunoblot data, gene-reporter assays, and proposed working model for Nrdp1-mediated polyubiquitination of Zap70 and inactivation of Zap70 by Sts1 and Sts2.

(a-c) Results in Fig. 8b were quantified by determining the band intensity and calculated as phosphorylated signaling molecules to total corresponding molecules. Data were presented as mean ± SD of three repeats (ANOVA). (d-f) EL4 cells were transfected with control (Ctrl) siRNAs, Sts1 and Sts2 siRNAs, Mock or Nrdp1 vectors, and the indicated reporter vectors for 48h. After treatment with anti-CD3 plus anti-CD28 antibodies for 4h, activation of reporters was evaluated and normalized against the pTA-Luc vector. Results were presented as mean ± SD of triplicate samples (ANOVA). (g-l) Results in Fig. 8f were quantified by determining the band intensity and calculated as phosphorylated signaling molecules to total corresponding molecules. Data were presented as mean ± SD of three repeats (ANOVA). ns, not significant; *, P < 0.05; **, P < 0.01; ***, P < 0.001. (m) The working model for Nrdp1-mediated polyubiquitination of Zap70 and inactivation of Zap70 was proposed. After recognition of antigen (Ag) peptide presented by MHC-I molecules on surface of antigen-presenting cells (APC) by TCR complex on CD8+ T cells, Zap70 was phosphorylated (indicated by “P”), leading to the activation of downstream signaling pathways and finally activation of NFAT, NF-κB and AP1 transcription factors (as illustrated in the left part). In the presence of Nrdp1, a complex formed between Nrdp1, Sts1, Sts2 and Zap70, among which Nrdp1 polyubiquitinates Zap70 (K33-linkage) and promotes the association of Sts1 and Sts2 (Sts1/2) with Zap70, and in turn, Sts1 and Sts2 dephosphorylates Zap70 by their tyrosine phosphatase (TPase) activity, finally leading to inactivation of Zap70 and termination of TCR signaling (as illustrated in the right part).

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Yang, M., Chen, T., Li, X. et al. K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8+ T cell activation. Nat Immunol 16, 1253–1262 (2015). https://doi.org/10.1038/ni.3258

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