Toll-interacting protein differentially modulates HIF1 and STAT5-mediated genes in fibroblasts
Toll-interacting protein differentially modulates HIF1 and STAT5-mediated genes in fibroblasts
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DOI：
10.1074/jbc.ra118.003382
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发表时间：
2018-08-03
影响因子：
4.8
通讯作者：
Li, Liwu
中科院分区：
文献类型：
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作者：
Kowalski, Elizabeth;Geng, Shuo;Li, Liwu
toll相互作用蛋白（Tollip）缺乏与复杂的炎症和感染性疾病有关，其机制尚不清楚。通过比较WT和Tollip缺陷小鼠胚胎成纤维细胞的基因表达谱，我们发现Tollip缺陷选择性地降低了炎症细胞因子白介素6 （IL-6）、IL-12和肿瘤坏死因子（TNF）的表达，但增强了这些细胞中脂肪酸结合蛋白4 （FABP4）的表达。我们还观察到，在tollip缺陷细胞中，缺氧诱导因子1- (HIF1)的表达减少，而信号换能器和转录激活因子5 （STAT5）的表达升高，这与这些细胞中炎症因子表达减少和FABP4表达增加有关。我们进一步发现，刺激HIF1活性需要泛素与Tollip的ER降解（CUE）结构域的偶联，因为Tollip CUE结构域突变细胞表现出HIF1和选定细胞因子水平的降低。已知Tollip介导自噬和溶酶体融合，本文中我们观察到Tollip的自噬功能是调节STAT5和FABP4表达所必需的。溶酶体融合抑制剂巴菲霉素A在WT成纤维细胞中增强了STAT5和FABP4的表达，而自噬激活剂torin 2在tollip缺陷成纤维细胞中降低了STAT5和FABP4的表达。综上所述，我们的研究揭示了Tollip对成纤维细胞中HIF1和STAT5表达的差异调节，这可能解释了Tollip对疾病发展的复杂和环境依赖性贡献。
Toll-interacting protein (Tollip) deficiency has been implicated in complex inflammatory and infectious diseases whose mechanisms are poorly understood. Comparing the gene expression profiles of WT and Tollip-deficient murine embryonic fibroblasts, we observed here that Tollip deficiency selectively reduces the expression of the inflammatory cytokines interleukin 6 (IL-6), IL-12, and tumor necrosis factor (TNF) but potentiates the expression of fatty acid-binding protein 4 (FABP4) in these cells. We also observed that expression of hypoxia-inducible factor 1- (HIF1) is reduced, whereas that of signal transducer and activator of transcription 5 (STAT5) is elevated, in Tollip-deficient cells, correlating with the decreased expression of inflammatory cytokines and increased expression of FABP4 in these cells. We further found that the coupling of ubiquitin to ER degradation (CUE) domain of Tollip is required for stimulating HIF1 activity, because Tollip CUE-domain mutant cells exhibited reduced levels of HIF1 and selected cytokines. Tollip is known to mediate autophagy and lysosome fusion, and herein we observed that Tollip's autophagy function is required for modulating STAT5 and FABP4 expression. Bafilomycin A, an inhibitor of lysosome fusion, enhanced STAT5 and FABP4 expression in WT fibroblasts, whereas torin 2, an activator of autophagy, reduced STAT5 and FABP4 expression in Tollip-deficient fibroblasts. Taken together, our study reveals that Tollip differentially modulates HIF1 and STAT5 expression in fibroblasts, potentially explaining the complex and context-dependent contribution of Tollip to disease development.