The Deubiquitinase USP17 Regulates the Stability and Nuclear Function of IL-33

Ni, Yingmeng; Tao, Lianqin; Chen, Chen; Song, Huihui; Li, Zhiyuan; Gao, Yayi; Nie, Jia; Piccioni, Miranda; Shi, Guochao; Li, Bin

doi:10.3390/ijms161126063

Cited by 39 publications

(29 citation statements)

References 30 publications

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“…TRAF2 and TRAF3 are known to undergo K63-linked self-ubiquitination for protein–protein interactions [ 25 , 26 ], therefore we also examined whether USP17 promotes TRAF2 and TRAF3 deubiquitination, and whether this deubiquitination activity is required for promoting inflammatory responses by USP17. It is known that cysteine residue 89 in the USP domain is required for the deubiquitination activity of USP17 [ 35 – 37 ], thus this cysteine was mutated into a serine residue (C89S) to generate an inactive mutant. When coexpressed in HEK293 cells, wild-type USP17 promoted K63-linked TRAF2 and TRAF3 deubiquitination, whereas the C89S mutant did not (Fig.…”

Section: Resultsmentioning

confidence: 99%

USP17 mediates macrophage-promoted inflammation and stemness in lung cancer cells by regulating TRAF2/TRAF3 complex formation

Yeh

Lai

et al. 2018

Oncogene

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Macrophage accumulation and inflammation in the lung owing to stresses and diseases is a cause of lung cancer development. However, molecular mechanisms underlying the interaction between macrophages and cancer cells, which drive inflammation and stemness in cancers, are poorly understood. In this study, we investigated the expression of ubiquitin-specific peptidase 17 (USP17) in lung cancers, and role of elevated USP17 in the interaction between macrophages and lung cancer cells. USP17 expression in lung cancers was associated with poor prognosis, macrophage, and inflammatory marker expressions. Macrophages promoted USP17 expression in cancer cells. TNFR-associated factor (TRAF) 2-binding and TRAF3-binding motifs were identified in USP17, through which it interacted with and disrupted the TRAF2/TRAF3 complex. This stabilized its client proteins, enhanced inflammation and stemness in cancer cells, and promoted macrophage recruitment. In different animal studies, co-injection of macrophages with cancer cells promoted USP17 expression in tumors and tumor growth. Conversely, depletion of macrophages in host animals by clodronate liposomes reduced USP17 expression and tumor growth. In addition, overexpression of USP17 in cancer cells promoted tumor growth and inflammation-associated and stemness-associated gene expressions in tumors. These results suggested that USP17 drives a positive-feedback interaction between macrophages and cancer cells to enhance inflammation and stemness in cancer cells, and promotes lung cancer growth.

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Section: Resultsmentioning

confidence: 99%

USP17 mediates macrophage-promoted inflammation and stemness in lung cancer cells by regulating TRAF2/TRAF3 complex formation

Yeh

Lai

et al. 2018

Oncogene

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“…We thus proposed that IL-33 may be a dual function protein, acting both extracellularly as an IL-1 family cytokine, and intracellularly as a nuclear factor regulating gene expression 2 . Nuclear functions of IL-33 in transcriptional regulation have been proposed in several recent studies 34 35 36 . However, to date, no large scale study has been performed to demonstrate a global role of endogenous nuclear IL-33 in the regulation of gene or protein expression.…”

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confidence: 99%

Extracellular IL-33 cytokine, but not endogenous nuclear IL-33, regulates protein expression in endothelial cells

Gautier

Cayrol

Farache

et al. 2016

Sci Rep

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IL-33 is a nuclear cytokine from the IL-1 family that plays important roles in health and disease. Extracellular IL-33 activates a growing number of target cells, including group 2 innate lymphoid cells, mast cells and regulatory T cells, but it remains unclear whether intracellular nuclear IL-33 has additional functions in the nucleus. Here, we used a global proteomic approach based on high-resolution mass spectrometry to compare the extracellular and intracellular roles of IL-33 in primary human endothelial cells, a major source of IL-33 protein in human tissues. We found that exogenous extracellular IL-33 cytokine induced expression of a distinct set of proteins associated with inflammatory responses in endothelial cells. In contrast, knockdown of endogenous nuclear IL-33 expression using two independent RNA silencing strategies had no reproducible effect on the endothelial cell proteome. These results suggest that IL-33 acts as a cytokine but not as a nuclear factor regulating gene expression in endothelial cells.

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“…Hou et al found that the E3 deubiquitinase USP21 is a positive regulator of GATA3 in asthma ( 23 ). Other studies indicate that the deubiquitinase USP17 regulates the stability and nuclear function of IL-33, and is also a positive regulator of retinoic acid-related orphan nuclear receptor γt (RORγt) in Th17 cells ( 24 , 25 ). In this study, we not only found an interaction between USP4 and IRF4, but also proved the effect of USP4 on the stabilization and deubiquitination of IRF4.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin specific peptidase 4 stabilizes interferon regulatory factor protein and promotes its function to facilitate interleukin-4 expression in T helper type 2 cells

Guo

et al. 2017

International Journal of Molecular Medicine

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We speculated that ubiquitin specific peptidase 4 (USP4) may deubiquitinate interferon regulatory factor 4 (IRF4) and affect T helper type 2 (Th2) cell function. This study aimed to validate this hypothesis. Here, the interaction between USP4 and IRF4 were analyzed by co-immunoprecipitation assay. The deubiquitin effect of USP4 on IRF4 was analyzed by the Ni-NTA pull down assay. Luciferase reporter gene constructs were used to analyze the effects of USP4, IRF4 and nuclear factor of activated T cell-2 (NFATc2) on the activation of the interleukin-4 (IL-4) promoter. Then, the Th2 cells were infected with sh-USP4 to analyze the effects of USP4 on the expression levels of IRF4 and Th2-related cytokines. Western blotting and RT-qPCR were used to detect the protein and mRNA expression levels, respectively. To determine the levels of IL-4 and IRF4 in rheumatic heart disease (RHD) patients, peripheral blood mononuclear cells (PBMCs) were separated by density gradient centrifugation from RHD patients and healthy controls, and flow cytometric analysis was performed. Our results validated the interaction between USP4 and IRF4, and effects of USP4 on stabilization and deubiquitination of IRF4 were also found. Importantly, USP4 and IRF4 synergized with NFATc2 to specifically enhance NFAT-mediated activation of the IL-4 promoter. USP4 knockdown not only decreased the expression level of IRF4, but also affected the expression level of Th2-related cytokines. Finally, the increased level of IL-4 and IRF4 in PBMCs of RHD patients were observed. On the whole, our data indicate that USP4 interacts with and deubiquitinates IRF4, and also stabilizes IRF4 protein and promotes IRF4 function to facilitate IL-4 expression in Th2 cells, which may be related to the pathological process of RHD.

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The Deubiquitinase USP17 Regulates the Stability and Nuclear Function of IL-33

Cited by 39 publications

References 30 publications

USP17 mediates macrophage-promoted inflammation and stemness in lung cancer cells by regulating TRAF2/TRAF3 complex formation

USP17 mediates macrophage-promoted inflammation and stemness in lung cancer cells by regulating TRAF2/TRAF3 complex formation

Extracellular IL-33 cytokine, but not endogenous nuclear IL-33, regulates protein expression in endothelial cells

Ubiquitin specific peptidase 4 stabilizes interferon regulatory factor protein and promotes its function to facilitate interleukin-4 expression in T helper type 2 cells

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