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

Yang, Mingjin; Chen, Taoyong; Li, Xuelian; Zhang, Yu; Tang, Songqing; Wang, Chen; Gu, Yan; Liu, Yanfang; Xu, Sheng; Li, Weihua; Zhang, Xuemin; Wang, JianLi; Cao, Xuetao

doi:10.1038/ni.3258

Cited by 80 publications

(95 citation statements)

References 49 publications

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“…Because dysregulation of these pathways impairs homoeostasis and immune responses, and can lead to lymphoma or autoimmunity, they are tightly regulated at multiple levels. E3 ligase-mediated ubiquitination is one of these essential regulatory mechanisms3456. TCR signalling and peripheral T-cell tolerance are known to be modulated via the ubiquitination of upstream elements, including TCRζ by Itch7, ZAP70 by the Cbl family and Nrdp1 (ref.…”

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confidence: 99%

K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression

et al. 2017

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T-cell proliferation is regulated by ubiquitination but the underlying molecular mechanism remains obscure. Here we report that Lys-48-linked ubiquitination of the transcription factor KLF4 mediated by the E3 ligase Mule promotes T-cell entry into S phase. Mule is elevated in T cells upon TCR engagement, and Mule deficiency in T cells blocks proliferation because KLF4 accumulates and drives upregulation of its transcriptional targets E2F2 and the cyclin-dependent kinase inhibitors p21 and p27. T-cell-specific Mule knockout (TMKO) mice develop exacerbated experimental autoimmune encephalomyelitis (EAE), show impaired generation of antigen-specific CD8+ T cells with reduced cytokine production, and fail to clear LCMV infections. Thus, Mule-mediated ubiquitination of the novel substrate KLF4 regulates T-cell proliferation, autoimmunity and antiviral immune responses in vivo.

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confidence: 99%

K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression

et al. 2017

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“…The molecular explanation(s) for the differences in degranulation by CD4 and CD8 T EM are unknown but experiments to determine this difference are an area of active investigation. One potential explanation could be a difference in the strength and/or duration of TCR signaling; it was recently shown that TCR-induced P-ZAP70 in mouse CD8 T cells is completely dephosphorylated within 30 minutes 30 . However, our assessment of the extent of ZAP70 phosphorylation suggests that the difference in degranulation between human CD4 and CD8 T EM interacting with antigen presented by EC cannot be explained by differences in the quantitative strength or duration of signaling.…”

Section: Discussionmentioning

confidence: 99%

Significant Differences in Antigen-Induced Transendothelial Migration of Human CD8 and CD4 T Effector Memory Cells

Manes

Pober

2016

ATVB

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Objective Circulating human T effector memory cell (TEM) recognition of non-self MHC molecules on allograft endothelial cells (EC) can initiate graft rejection despite elimination of professional antigen presenting cells necessary for naïve T cell activation. Our prior studies of CD4 TEM have established that engagement of the T cell receptor (TCR) not only activates T cells but also triggers transendothelial migration (TEM) by a process that is distinct from that induced by activating chemokine receptors (CR) on T cells, being slower, requiring microtubule organizing center (MTOC)-directed cytolytic granule polarization to and release from the leading edge of the T cell, and requiring engagement of proteins of the EC lateral border recycling compartment (LBRC). While CD4 TEM may contribute to acute allograft rejection, the primary effectors are alloreactive CD8 TEM. Whether and how TCR engagement affects TEM of human CD8 TEM is unknown. Approach and Results We modeled TEM of CD8 TEM across cultured human microvascular EC engineered to present superantigen under conditions of venular shear stress in vitro in a flow chamber. Here we report that TCR engagement can also induce TEM of this population that similarly differs from CR-driven TEM with regard to kinetics, morphological manifestations, and MTOC dynamics as with CD4 TEM. However, CD8 TEM do not require either cytolytic granule release or interactions with proteins of the LBRC. Conclusions These results imply that therapeutic strategies designed to inhibit TCR-driven recruitment based on targeting granule release or components of the LBRC will not affect CD8 TEM and are unlikely to block acute rejection in the clinic.

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“…Our previous studies and others have demonstrated that Nrdp1 plays a crucial role in cardiac myocardial and neuronal response to ischemic or immune stimuli [11,12,18,19]. Accumulating evidence indicates that Nrdp1-dependent proteolysis of its substrates, such as ErbB3, BRUCE, MyD88, Parkin, eIF3-f, and Clec16a, could constitute the important events to regulate cell growth, inflammation, and tumor genesis [9,11,15,31,32].…”

Section: Discussionmentioning

confidence: 99%

“…Nrdp1 has ubiquitin ligase activity and targets proteins such as ErbB3, BRUCE/apollon, Parkin, MyD88, and Zap70 for ubiquitin-mediated degradation [8,9,10,11,12]. Nrdp1 has been reported to be involved in cell growth, tumor suppression, inflammation response, and immune regulation through controlling targeted protein levels [12,13,14,15,16,17]. We have previously shown that the overexpression of Nrdp1 in the heart tissue induced rapid inactivation of cardiac ErbB3 and exacerbated myocardial apoptosis, inflammation, and tissue infarction in a rat model of heart ischemia/reperfusion injury [18].…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Effects of E3 Ligase Nrdp1 on Hypertrophy in Neonatal Rat Cardiomyocytes by Microarray and Integrated Gene Network Analysis

Zhang

Su²,

Zhang³

2016

Cardiology

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Objective: Neuregulin receptor degradation protein-1 (Nrdp1) is a novel E3 ubiquitin ligase, and we have previously shown that overexpression of Nrdp1 increased cardiomyocyte injury. However, the role of Nrdp1 in myocardial hypertrophy is unclear. In the present study, we clarified the molecular mechanisms of angiotensin II (Ang II)-induced cardiomyocyte hypertrophy regulated by Nrdp1 based on genome-wide transcriptional analysis. Methods: Neonatal rat cardiomyocytes were infected with adenoviruses containing green fluorescent protein (Ad-GFP) or wild-type Nrdp1 (Ad-Nrdp1), and then treated with Ang II for 36 h. Detection of differentially expressed genes was achieved with an Affymetrix Rat Gene 2.0 Array and Cluster and Java TreeView software. Results and Conclusion: Microarray data analysis demonstrated that Nrdp1 overexpression affected the expression of 12,140 mRNA genes in Ang II-induced cardiomyocyte hypertrophy, including the upregulation of 12,044 and the downregulation of 96. Gene ontology and globe signal transduction network analysis showed that Nrdp1 affected the expression of many genes related to stimulus response, the cell receptor pathway, and cell growth. Pathway network analysis identified myocardial metabolism, DNA replication, and the cell cycle as the most important pathways targeted by Nrdp1. lncRNA-mRNA coexpression network analysis showed that two core lncRNAs, NONRATT057160 and NONRATT054243, were involved in cardiomyotrophy regulated by Nrdp1 in cardiomyocytes. Taken together, these data provide compelling clues for further exploration of the function of Nrdp1 in heart disease.

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

Cited by 80 publications

References 49 publications

K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression

K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression

Significant Differences in Antigen-Induced Transendothelial Migration of Human CD8 and CD4 T Effector Memory Cells

Transcriptional Effects of E3 Ligase Nrdp1 on Hypertrophy in Neonatal Rat Cardiomyocytes by Microarray and Integrated Gene Network Analysis

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