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

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

doi:10.1038/ni.3258

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

Nat Immunol. 2015 Dec;16(12):1253-62. doi: 10.1038/ni.3258. Epub 2015 Sep 21.

Authors

Mingjin Yang^{1

2}, Taoyong Chen², Xuelian Li², Zhou Yu³, Songqing Tang³, Chen Wang², Yan Gu², Yanfang Liu², Sheng Xu², Weihua Li⁴, Xuemin Zhang⁴, Jianli Wang³, Xuetao Cao^{1

2}

Affiliations

¹ National Key Laboratory of Medical Molecular Biology &Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.
² National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
³ Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
⁴ Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.

PMID: 26390156
DOI: 10.1038/ni.3258

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / metabolism
Carrier Proteins / genetics
Carrier Proteins / immunology*
Carrier Proteins / metabolism
Lymphocyte Activation / genetics
Lymphocyte Activation / immunology*
Lysine / genetics
Lysine / immunology*
Lysine / metabolism
Mice, Congenic
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Confocal
Phosphorylation / immunology
Polyubiquitin / immunology
Polyubiquitin / metabolism
Protein Binding / immunology
RNA Interference
Receptors, Antigen, T-Cell / genetics
Receptors, Antigen, T-Cell / immunology
Receptors, Antigen, T-Cell / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / genetics
Signal Transduction / immunology
Transcriptome / genetics
Transcriptome / immunology
Ubiquitin-Protein Ligases
Ubiquitination / immunology
ZAP-70 Protein-Tyrosine Kinase / immunology*
ZAP-70 Protein-Tyrosine Kinase / metabolism

Substances

Carrier Proteins
Receptors, Antigen, T-Cell
Polyubiquitin
Rnf41 protein, mouse
Ubiquitin-Protein Ligases
ZAP-70 Protein-Tyrosine Kinase
Zap70 protein, mouse
Lysine

Associated data

GEO/GSE70393