Absence of Grail promotes CD8+ T cell 
anti-tumour activity

Haymaker, Cara; Yang, Yi; Wang, Junmei; Zou, Qiang; Sahoo, Anupama; Alekseev, Andrei; Singh, Divyendu; Ritthipichai, Krit; Hailemichael, Yared; Hoang, O.N.; Qin, Hong; Schluns, Kimberly S.; Wang, Zhihui; Overwijk, Willem W.; Sun, Shao Cong; Bernatchez, Chantale; Kwak, Larry W.; Neelapu, Sattva S.; Nurieva, Roza

doi:10.1038/s41467-017-00252-w

Cited by 22 publications

(30 citation statements)

References 36 publications

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“…In mouse models, deletion of NR4A1, Blimp-1, Cbl-b, NFAT, TSC1, GRAIL, or Egr-2 impairs induction of T cell tolerance in vivo (Haymaker et al, 2017; Jeon et al, 2004; Liu et al, 2019; Macian et al, 2002; Martins et al, 2008; Xie et al, 2012; Zheng et al, 2012). Overexpression of c-Jun in T cells renders them resistant to exhaustion (Lynn et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Three-dimensional genome structure and chromatin accessibility reorganization during in vivo induction of human T cell tolerance

Guo

Hou

et al. 2020

Preprint

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Achieving T cell tolerance is a pivotal goal for the field of transplantation and autoimmune diseases. Here, we characterized the gene expression profiles, 3D genome architecture and chromatin accessibility in human steady-state and tolerant T cells, which had been induced in healthy donors by granulocyte-colony-stimulating factor in vivo. We provided the first high-resolution 3D genomic landscape of human tolerant T cells in vivo and identified highly expressed suppressor of cytokine signaling 1 (SOCS1), which is essential for maintaining T cell tolerance and was validated by ex vivo experiments. Mechanistically, SOCS1 is activated by STAT3, which mediates a new interaction between the SOCS1 locus and downstream super-enhancers and is accompanied by the disruption of the CTCF loop between the SOCS1 locus and upstream heterochromatin. This competitive regulation pattern between STAT3 and CTCF is present in the whole genome.Our study defines a regulatory model of transcription factors and provides insight into the induction of immune tolerance.3

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Section: Discussionmentioning

confidence: 99%

Three-dimensional genome structure and chromatin accessibility reorganization during in vivo induction of human T cell tolerance

Guo

Hou

et al. 2020

Preprint

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“…21 RNF128 has recently been documented to be involved in the progression of diverse cancers, including esophageal cancer, 12 melanoma, 13 urothelial carcinoma 14 and lymphoma. 11 Nonetheless, the role of RNF128 in HCC remains unexplored. Here, we clarified the function and mechanism of RNF128 in HCC for the first time.…”

Section: Dovepressmentioning

confidence: 99%

“…Previous studies showed that lack of RNF128 enhanced the antitumor activity of CD8+ T cells in lymphomas. 11 All these suggest that RNF128 may modulate additional signal transduction pathways or participate in other biological processes in HCC, which needs to be explored further.…”

Section: Dovepressmentioning

confidence: 99%

“…Deficiency of RNF128 promotes anti-tumor immune response of CD8+ T cells. 11 Besides that, RNF128 interacts with p53 and activates EGFR/MAPK/MMP-2 pathway, promoting the invasiveness and migratory ability of esophageal squamous cell carcinoma. 12 In melanoma, however, RNF128 regulates Wnt/β-catenin signaling to suppress EMT and stemness through a mechanism involving CD44 ubiquitination.…”

Section: Introductionmentioning

confidence: 99%

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<p>RNF128 Promotes Malignant Behaviors via EGFR/MEK/ERK Pathway in Hepatocellular Carcinoma</p>

Bai

Zhang

Peng

et al. 2020

OTT

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Background: The ubiquitin-proteasome system participates in the pathogenesis and progression of hepatocellular carcinoma (HCC). As an E3 ubiquitin ligase, RNF128 has been proved vital in carcinogenesis, whereas, little is known about the oncogenic mechanisms of RNF128 in HCC. Materials and Methods: Through tissue microarray from HCC patients, we analyzed RNF128 expression and its relationship with clinical outcomes in HCC. Western blot and quantitative realtime polymerase chain reaction (qRT-PCR) were performed to examine expression levels of RNF128 in HCC tissues and cell lines. Effects of RNF128 on HCC cellular biological functions and the potential mechanism were evaluated through knockdown and overexpression assays in vitro and in vivo methods. Results: RNF128 expression was found to be remarkably elevated in HCC tissues compared with adjacent normal tissues. Furthermore, the overexpression of RNF128 enhanced hepatoma cells proliferation, colony formation, migration, invasion, and apoptotic resistance both in vitro and in vivo. Mechanistically, RNF128 activated EGFR/MEK/ERK signaling pathway and the EGFR inhibitor, gefitinib partially reversed RNF128-enhanced proliferation, invasion, and migration in hepatoma cells. Conclusion: RNF128 promotes HCC progression by activating EGFR/MEK/ERK signaling pathway, which might function as a novel prognostic molecular signature with the potential to be a candidate therapeutic target for HCC patients.

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“…Ubiquitination is one of the most common pathway that modulates protein proteolysis. Ubiquitination is implicated in the pathogenesis of cancer via regulating oncogenes, tumor suppressor genes and immune-related genes 18–20. Studies on ubiquitination in melanoma provide novel therapeutic targets for cancer.…”

Section: Introductionmentioning

confidence: 99%

<p>NEDD4 Negatively Regulates GITR via Ubiquitination in Immune Microenvironment of Melanoma</p>

Guo

Yang

Lei

et al. 2019

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IntroductionMelanoma is a common skin cancer that is usually associated with poor clinical outcomes. Recently, the immune checkpoint GITR has been identified as a promising target for immunotherapy of melanoma. In this study, we aimed to investigate the post-translational regulation mechanism of GITR in melanoma.MethodsWestern blotting was used to evaluate the protein expression of NEDD4, GITR and Foxp3. Real-time PCR (RT-PCR) was performed to determine expression levels of NEDD4, GITR, Foxp3 and IL-2. Cell viability was detected by MTT assay. The ubiquitination of GITR was evaluated by immunoprecipitation. NEDD4 expression data and melanoma survival data were obtained from The Cancer Genome Atlas (TCGA) and cBioPortal databases.ResultsWe demonstrate that E3 ligase NEDD4 binds to GITR and mediates ubiquitination and degradation of GITR. Overexpression of NEDD4 inhibits anti-tumor immunity mediated by T cells against melanoma cells. We also found that the expression of NEDD4 is increased in metastatic melanoma. High NEDD4 expression level is correlated with the poor prognosis of melanoma patients.DiscussionIn summary, our findings demonstrated that E3 ligase NEDD4 mediates ubiquitination and degradation of GITR and suppresses T-cell-mediated-killings on melanoma cells. Our work highlighted the E3 ligase NEDD4 as a novel prognosis biomarker and therapeutic target for melanoma.

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Absence of Grail promotes CD8+ T cell anti-tumour activity

Cited by 22 publications

References 36 publications

Three-dimensional genome structure and chromatin accessibility reorganization during in vivo induction of human T cell tolerance

Three-dimensional genome structure and chromatin accessibility reorganization during in vivo induction of human T cell tolerance

<p>RNF128 Promotes Malignant Behaviors via EGFR/MEK/ERK Pathway in Hepatocellular Carcinoma</p>

<p>NEDD4 Negatively Regulates GITR via Ubiquitination in Immune Microenvironment of Melanoma</p>

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