Regulation of inflammatory signaling by the ST6Gal-I sialyltransferase.
Regulation of inflammatory signaling by the ST6Gal-I sialyltransferase.
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DOI：
10.1371/journal.pone.0241850
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发表时间：
2020
期刊：
影响因子：
3.7
通讯作者：
Bellis SL
中科院分区：
文献类型：
--
作者：
Holdbrooks AT;Ankenbauer KE;Hwang J;Bellis SL
ST 6 Gal-I唾液酸转移酶是一种将α2-6-连接的唾液酸添加到N-糖基化蛋白的酶，调节多种免疫过程。然而，受体唾液酸化对炎症信号传导的贡献尚未得到充分研究。在目前的研究中，我们发现了ST 6 Gal-I通过两个主要的炎症通路NFκB和JAK/STAT促进持续信号传导的作用。使用U937单核细胞模型，我们确定ST 6 Gal-I表达的敲低（KD）对TNF（≤ 30 min）快速激活NFκB没有影响，而在ST 6 Gal-I-KD细胞中，TNF诱导的NFκB长期激活（2-6 h）减少。这些数据与先前在上皮细胞中的工作一致，表明TNFR 1的α2-6唾液酸化抑制TNF依赖性NFκB活化。与TNF类似，ST 6 Gal-I KD可长期而非短期抑制LPS诱导的NFκB活化。ST 6 Gal-I KD细胞还表现出LPS引起的长期IRF 3和STAT 3活化降低。鉴于ST 6 Gal-I活性调节LPS依赖性信号传导，我们使用SNA（α2-6唾液酸特异性凝集素）进行下拉测定，以显示LPS受体TLR 4是ST 6 Gal-I唾液酸化的底物。我们接下来评估了IFNγ、IL-6和GM-CSF的信号传导，发现ST 6 Gal-I-KD对这些细胞因子诱导的STAT活化具有有限的作用。为了证实这些发现，在来自骨髓特异性缺失ST 6 Gal-I（LysMCre/ST 6 Gal-Ifl/fl）的小鼠的骨髓来源的巨噬细胞（BMDM）中监测信号传导。与来自U937细胞的数据一致，ST 6 Gal-I敲除的BMDM显示TNF和LPS对NFκB的长期激活减少，并且减少了长期LPS依赖性STAT 3激活。然而，IFNγ、IL-6和GM-CSF诱导的STAT活化在野生型和ST 6 Gal-I敲除的BMDM中是相当的。这些结果暗示了ST 6 Gal-I介导的受体唾液酸化延长了选择的信号级联的活性，包括TNF/NFκB、LPS/NFκB和LPS/STAT 3，为ST 6 Gal-I在调节单核细胞的炎症表型中的作用提供了新的见解。
The ST6Gal-I sialyltransferase, an enzyme that adds α2-6-linked sialic acids to N-glycosylated proteins, regulates multiple immunological processes. However, the contribution of receptor sialylation to inflammatory signaling has been under-investigated. In the current study, we uncovered a role for ST6Gal-I in promoting sustained signaling through two prominent inflammatory pathways, NFκB and JAK/STAT. Using the U937 monocytic cell model, we determined that knockdown (KD) of ST6Gal-I expression had no effect on the rapid activation of NFκB by TNF (≤ 30 min), whereas long-term TNF-induced NFκB activation (2–6 hr) was diminished in ST6Gal-I-KD cells. These data align with prior work in epithelial cells showing that α2–6 sialylation of TNFR1 prolongs TNF-dependent NFκB activation. Similar to TNF, long-term, but not short-term, LPS-induced activation of NFκB was suppressed by ST6Gal-I KD. ST6Gal-I KD cells also exhibited reduced long-term IRF3 and STAT3 activation by LPS. Given that ST6Gal-I activity modulated LPS-dependent signaling, we conducted pull-down assays using SNA (a lectin specific for α2–6 sialic acids) to show that the LPS receptor, TLR4, is a substrate for sialylation by ST6Gal-I. We next assessed signaling by IFNγ, IL-6 and GM-CSF, and found that ST6Gal-I-KD had a limited effect on STAT activation induced by these cytokines. To corroborate these findings, signaling was monitored in bone marrow derived macrophages (BMDMs) from mice with myeloid-specific deletion of ST6Gal-I (LysMCre/ST6Gal-Ifl/fl). In agreement with data from U937 cells, BMDMs with ST6Gal-I knockout displayed reduced long-term activation of NFκB by both TNF and LPS, and diminished long-term LPS-dependent STAT3 activation. However, STAT activation induced by IFNγ, IL-6 and GM-CSF was comparable in wild-type and ST6Gal-I knockout BMDMs. These results implicate ST6Gal-I-mediated receptor sialylation in prolonging the activity of select signaling cascades including TNF/NFκB, LPS/NFκB, and LPS/STAT3, providing new insights into ST6Gal-I’s role in modulating the inflammatory phenotype of monocytic cells.
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影响因子：
16.6
作者：
Li, Ming;Foo, Jia-Nee;Wang, Jin-Quan;Low, Hui-Qi;Tang, Xue-Qing;Toh, Kai-Yee;Yin, Pei-Ran;Khor, Chiea-Chuen;Goh, Yu-Fen;Irwan, Ishak D.;Xu, Ri-Cong;Andiappan, Anand K.;Bei, Jin-Xin;Rotzschke, Olaf;Chen, Meng-Hua;Cheng, Ching-Yu;Sun, Liang-Dan;Jiang, Geng-Ru;Wong, Tien-Yin;Lin, Hong-Li;Aung, Tin;Liao, Yun-Hua;Saw, Seang-Mei;Ye, Kun;Ebstein, Richard P.;Chen, Qin-Kai;Shi, Wei;Chew, Soo-Hong;Chen, Jian;Zhang, Fu-Ren;Li, Sheng-Ping;Xu, Gang;Tai, E. Shyong;Wang, Li;Chen, Nan;Zhang, Xue-Jun;Zeng, Yi-Xin;Zhang, Hong;Liu, Zhi-Hong;Yu, Xue-Qing;Liu, Jian-Jun
通讯作者：
Liu, Jian-Jun
影响因子：
4.8
作者：
Correia, JD;Ulevitch, RJ
通讯作者：
Ulevitch, RJ
影响因子：
11.4
作者：
BARBARA, JAJ;SMITH, WB;LOPEZ, AF
通讯作者：
LOPEZ, AF
影响因子：
4.8
作者：
Meng, Jianmin;Parroche, Peggy;McKnight, C. James
通讯作者：
McKnight, C. James
影响因子：
64.5
作者：
Micheau, O;Tschopp, J
通讯作者：
Tschopp, J