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

• DOI: 10.1038/ni.3258
• Publication Date: 2015-09-21T12:24:10Z
• Authors: Mingjin Yang; Taoyong Chen; Xuelian Li; Zhou Yu; Songqing Tang; Chen Wang; Yan Gu; Yanfang Liu; Sheng Xu; Weihua Li; Xuemin Zhang; Jianli Wang; Xuetao Cao
• Keywords: Mice, Knockout; 0303 health sciences; Microscopy, Confocal; ZAP-70 Protein-Tyrosine Kinase; Reverse Transcriptase Polymerase Chain Reaction; Lysine; Ubiquitin-Protein Ligases; Receptors, Antigen, T-Cell; Ubiquitination; CD8-Positive T-Lymphocytes; Lymphocyte Activation; Mice, Inbred C57BL; Mice, Congenic; 03 medical and health sciences; Animals; RNA Interference; Phosphorylation; Carrier Proteins; Polyubiquitin; Transcriptome; Protein Binding; Signal Transduction

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.