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TRAF3IP3 at the trans-Golgi network regulates NKT2 maturation via the MEK/ERK signaling pathway.

ABSTRACT: Thymic natural killer T (NKT)2 cells are a subset of invariant NKT cells with PLZF^hiGATA3^hiIL-4⁺. The differentiation of NKT2 cells is not fully understood. In the present study, we report an important role of TRAF3-interacting protein 3 (TRAF3IP3) in the functional maturation and expansion of committed NKT2s in thymic medulla. Mice with T-cell-specific deletion of TRAF3IP3 had decreased thymic NKT2 cells, decreased IL-4-producing peripheral iNKTs, and defects in response to α-galactosylceramide. Positive selection and high PLZF expression in CD24⁺CD44^- and CCR7⁺CD44^- immature iNKTs were not affected. Only CD44^hiNK1.1^- iNKTs in Traf3ip3^-/- mice showed reduced expression of Egr2, PLZF, and IL-17RB, decreased proliferation, and reduced IL-4 production upon stimulation. This Egr2 and IL-4 expression was augmented by MEK1/ERK activation in iNKTs, and TRAF3IP3 at the trans-Golgi network recruited MEK1 and facilitated ERK phosphorylation and nuclear translocation. LTβR-regulated bone marrow-derived nonlymphoid cells in the medullary thymic microenvironment were required for MEK/ERK activation and NKT2 maturation. These data demonstrate an important functional maturation process in NKT2 differentiation that is regulated by MEK/ERK signaling at the trans-Golgi network.

SUBMITTER: Zhang X

PROVIDER: S-EPMC7109081 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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TRAF3IP3 at the trans-Golgi network regulates NKT2 maturation via the MEK/ERK signaling pathway.

Zhang Xinwei X Wang Ke K Zhao Weijia W Cao Li L Zhang Shusong S Jin Rong R Sun Xiuyuan X Hao Jie J Huang Xiaojun X Zhu Mingzhao M Wu Hounan H Zhao Hongshan H Ge Qing Q

Cellular & molecular immunology 20190510 4

Thymic natural killer T (NKT)2 cells are a subset of invariant NKT cells with PLZFhiGATA3hiIL-4+. The differentiation of NKT2 cells is not fully understood. In the present study, we report an important role of TRAF3-interacting protein 3 (TRAF3IP3) in the functional maturation and expansion of committed NKT2s in thymic medulla. Mice with T-cell-specific deletion of TRAF3IP3 had decreased thymic NKT2 cells, decreased IL-4-producing peripheral iNKTs, and defects in ...[more]

PMID: 31076725

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Project description:TRAF3IP3 was reportedly associated with poor prognosis in patients with melanoma; however, its role in glioma is unknown. We aimed to demonstrate the relationship between TRAF3IP3 and glioma and to investigate the potential role of TRAF3IP3 in glioma. Datasets were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We used the Wilcoxon rank-sum test to compared TRAF3IP3 expression in normal and glioma tissues. Kaplan-Meier analysis was performed to evaluate the correlation between TRAF3IP3 and patient survival rate. Gene set enrichment analysis (GSEA) was used to annotate the biological function of TRAF3IP3 in glioma. We also examined the effects of TRAF3IP3 on glioma progression, including characteristics such as cell proliferation, migration, and invasion, using cell proliferation, wound healing, and Transwell assays, respectively, paired with in vitro glioma cell lines and in vivo mouse xenograft models to determine the molecular mechanisms underlying these effects. High TRAF3IP3 expression in glioma tissues was associated with patients with neoplasm cancer tissue source site, and poorer overall survival (OS) (p = 0.03), which was validated using TCGA. GSEA revealed the enrichment of neuroactive ligand-receptor interactions, the olfactory pathway, proteasome pathway, cytokine-cytokine receptor interactions, and calcium signaling pathway in the TRAF3IP3 high-expression phenotype. TRAF3IP3 knockdown markedly suppressed the proliferation, migration, and invasion abilities of U251 glioma cells, whereas TRAF3IP3 overexpression notably promoted the progression of U118 cell tumors. Mechanistic studies revealed that TRAF3IP3 upregulated p-ERK expression in glioma cells. Notably, the ERK signaling pathway inhibitor U0126 drastically attenuated the effects of TRAF3IP3 on p-ERK and markedly blocked its tumor-promoting activity. TRAF3IP3 overexpression also promoted in vivo tumor growth in a nude mouse xenograft model. Collectively, TRAF3IP3 stimulates glioma cell proliferation, migration, and invasion, at least partly by activating the ERK signaling pathway. We hypothesize that TRAF3IP3 may participate in glioma development via the ERK signaling pathway and that elevated TRAF3IP3 expression may serve as a potential biomarker for glioma prognosis.

Dataset Information

TRAF3IP3 at the trans-Golgi network regulates NKT2 maturation via the MEK/ERK signaling pathway.

Publications

TRAF3IP3 at the trans-Golgi network regulates NKT2 maturation via the MEK/ERK signaling pathway.

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