The inhibition of N-glycosylation of glycoprotein 130 molecule abolishes STAT3 activation by IL-6 family cytokines in cultured cardiac myocytes.
The inhibition of N-glycosylation of glycoprotein 130 molecule abolishes STAT3 activation by IL-6 family cytokines in cultured cardiac myocytes.
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DOI：
10.1371/journal.pone.0111097
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Fujio Y
中科院分区：
文献类型：
--
作者：
Matsuo R;Morihara H;Mohri T;Murasawa S;Takewaki K;Nakayama H;Maeda M;Fujio Y
白细胞介素-6（IL-6）家族细胞因子在心脏病理应激保护中起重要作用。IL-6细胞因子与其特异性受体结合并激活糖蛋白130（gp 130）（一种常见受体），随后通过Janus激酶（JAK）进一步激活STAT 3和细胞外信号调节激酶（ERK）1/2;然而，gp 130糖基化在心肌细胞中的重要性仍有待阐明。在这项研究中，我们研究了gp 130糖基化的生物学意义，使用衣霉素（Tm），参与N-连接糖基化酶的抑制剂。在心肌细胞中，用Tm处理完全取代了糖基化形式的gp 130与其非糖基化的。Tm处理抑制白血病抑制因子（LIF）介导的STAT 3和ERK 1/2的活化。类似地，IL-11在Tm存在下不能激活STAT 3和ERK 1/2。有趣的是，Tm抑制JAK 1和2的活化，而不影响JAK的内源性抑制剂细胞因子信号转导抑制因子（SOCS）和蛋白酪氨酸磷酸酶1B（PTP 1B）的表达。为了排除Tm通过抑制LIF和IL-11特异性受体的糖基化而阻断LIF和IL-11信号的可能性，我们研究了IL-6和可溶性IL-6受体（sIL-6 R）的刺激是否可以在Tm处理的心肌细胞中阻断它们的信号，并且发现这种刺激不能激活下游信号。总的来说，这些发现表明，糖基化的gp 130是必不可少的IL-6家族细胞因子在心肌细胞中的信号转导。
Interleukin-6 (IL-6) family cytokines play important roles in cardioprotection against pathological stresses. IL-6 cytokines bind to their specific receptors and activate glycoprotein 130 (gp130), a common receptor, followed by further activation of STAT3 and extracellular signal-regulated kinase (ERK)1/2 through janus kinases (JAKs); however the importance of glycosylation of gp130 remains to be elucidated in cardiac myocytes. In this study, we examined the biological significance of gp130 glycosylation using tunicamycin (Tm), an inhibitor of enzyme involved in N-linked glycosylation. In cardiomyocytes, the treatment with Tm completely replaced the glycosylated form of gp130 with its unglycosylated one. Tm treatment inhibited leukemia inhibitory factor (LIF)-mediated activation of STAT3 and ERK1/2. Similarly, IL-11 failed to activate STAT3 and ERK1/2 in the presence of Tm. Interestingly, Tm inhibited the activation of JAKs 1 and 2, without influencing the expression of suppressor of cytokine signalings (SOCSs) and protein-tyrosine phosphatase 1B (PTP1B), which are endogenous inhibitors of JAKs. To exclude the possibility that Tm blocks LIF and IL-11 signals by inhibiting the glycosylation of their specific receptors, we investigated whether the stimulation with IL-6 plus soluble IL-6 receptor (sIL-6R) could transduce their signals in Tm-treated cardiomyocytes and found that this stimulation was unable to activate the downstream signals. Collectively, these findings indicate that glycosylation of gp130 is essential for signal transduction of IL-6 family cytokines in cardiomyocytes.
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