title: K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8(+) T cell activation.
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.
authors.affiliation: National Key Laboratory of Medical Molecular Biology &Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.|National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Mingjin
authors.initials: M
authors.lastname: Yang
authors.affiliation: National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Taoyong
authors.initials: T
authors.lastname: Chen
authors.affiliation: National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Xuelian
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Songqing
authors.initials: S
authors.lastname: Tang
authors.affiliation: National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
authors.affiliation: National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Xu
authors.affiliation: Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.affiliation: Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: Xuemin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Jianli
authors.initials: J
authors.lastname: Wang
authors.affiliation: National Key Laboratory of Medical Molecular Biology &Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.|National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008239:Lysine / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010766:Phosphorylation / Q000276:immunology; D025821:Polyubiquitin / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D034622:RNA Interference; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D059467:Transcriptome / Q000235:genetics / Q000276:immunology; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination / Q000276:immunology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000276:immunology* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D011948:Receptors, Antigen, T-Cell; D025821:Polyubiquitin; C435904:Rnf41 protein, mouse; D044767:Ubiquitin-Protein Ligases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D008239:Lysine