SUMOylation pathway alteration coupled with downregulation of SUMO E2 enzyme at mucosal epithelium modulates inflammation in inflammatory bowel disease.
SUMOylation pathway alteration coupled with downregulation of SUMO E2 enzyme at mucosal epithelium modulates inflammation in inflammatory bowel disease.
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DOI：
10.1098/rsob.170024
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发表时间：
2017-06
期刊：
影响因子：
5.8
通讯作者：
Srikanth CV
中科院分区：
文献类型：
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作者：
Mustfa SA;Singh M;Suhail A;Mohapatra G;Verma S;Chakravorty D;Rana S;Rampal R;Dhar A;Saha S;Ahuja V;Srikanth CV
翻译后修饰途径如SUMO化是所有细胞过程和组织稳态不可或缺的。我们研究了SUMO化在克罗恩病（CD）和溃疡性结肠炎（UC）（炎症性肠病（IBD）的两种主要形式）上皮信号传导中的可能参与。最初，在由葡聚糖硫酸钠（DSS小鼠）诱导的IBD小鼠模型中，我们观察到炎症伴随着结肠上皮的整体SUMO化的降低。观察到的SUMO化改变是由于唯一的SUMO E2酶（Ubc9）的减少。质谱分析显示，DSS小鼠中存在不同的SUMO结合蛋白质组（SUMO结合蛋白质组），并改变了关键的细胞调节因子，包括主激酶Akt1。上皮细胞中Ubc9的敲低导致炎症基因表达的显著激活，这一现象通过Akt1及其SUMO化形式的减少而起作用。重要的是，在人CD和UC患者的内窥镜活检样本（N = 66）中也观察到Ubc 9和Akt1的强烈降低。此外，具有最大疾病指数的患者总是伴有Ubc9或SUMO化Akt1的严重降低。Ubc9功能严重受损的粘液组织显示出更高水平的促炎细胞因子和受损的伤口愈合标记物。因此，我们的研究结果揭示了一个重要的和以前未描述的SUMO化途径，涉及Ubc9和Akt1在炎症性肠病上皮炎症信号的调制作用。
Post-translational modification pathways such as SUMOylation are integral to all cellular processes and tissue homeostasis. We investigated the possible involvement of SUMOylation in the epithelial signalling in Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD). Initially in a murine model of IBD, induced by dextran–sulfate–sodium (DSS mice), we observed inflammation accompanied by a lowering of global SUMOylation of colonic epithelium. The observed SUMOylation alteration was due to a decrease in the sole SUMO E2 enzyme (Ubc9). Mass-spectrometric analysis revealed the existence of a distinct SUMOylome (SUMO-conjugated proteome) in DSS mice with alteration of key cellular regulators, including master kinase Akt1. Knocking-down of Ubc9 in epithelial cells resulted in dramatic activation of inflammatory gene expression, a phenomenon that acted via reduction in Akt1 and its SUMOylated form. Importantly, a strong decrease in Ubc9 and Akt1 was also seen in endoscopic biopsy samples (N = 66) of human CD and UC patients. Furthermore, patients with maximum disease indices were always accompanied by severely lowered Ubc9 or SUMOylated-Akt1. Mucosal tissues with severely compromised Ubc9 function displayed higher levels of pro-inflammatory cytokines and compromised wound-healing markers. Thus, our results reveal an important and previously undescribed role for the SUMOylation pathway involving Ubc9 and Akt1 in modulation of epithelial inflammatory signalling in IBD.