IQ Motif-Containing GTPase-Activating Protein 2 (IQGAP2) Is a Novel Regulator of Colonic Inflammation in Mice.
IQ Motif-Containing GTPase-Activating Protein 2 (IQGAP2) Is a Novel Regulator of Colonic Inflammation in Mice.
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DOI：
10.1371/journal.pone.0129314
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Schmidt VA
中科院分区：
文献类型：
--
作者：
Ghaleb AM;Bialkowska AB;Snider AJ;Gnatenko DV;Hannun YA;Yang VW;Schmidt VA
IQ模体包含GTP酶激活蛋白2（IQGAP 2）是一种多结构域支架蛋白，其通过并置Rho GTP酶和Ca 2 +/钙调蛋白信号在细胞骨架调节中起作用。虽然IQGAP 2抑制肝脏中的肿瘤发生，但其在胃肠道的病理生理学中的作用仍未被探索。在这里，我们报告IQGAP 2是结肠炎症反应所必需的。缺乏Iqgap 2基因的小鼠（Iqgap 2-/-小鼠）对化学诱导的结肠炎具有抗性。与野生型对照组不同，用3%葡聚糖硫酸钠（DSS）水溶液处理13天的Iqgap 2-/-小鼠未显示结肠上皮损伤。从机制上讲，对结肠炎的抵抗与结肠NF-κB信号传导和IL-6合成的抑制有关，沿着Iqgap 2-/-小鼠中中性粒细胞和巨噬细胞的产生和募集减少。最后，在炎症性肠病（IBD）患者的结肠中发现IQGAP 2表达的改变。我们的研究结果表明，IQGAP 2在两个不同的水平上促进炎症反应;局部，通过TLR 4/NF-κB信号通路在结肠上皮中，和全身，通过控制骨髓免疫细胞的成熟和募集。这项工作确定了一个新的机制，结肠炎症信号转导支架蛋白IQGAP 2介导的。IQGAP 2结构域特异性阻断剂可能代表了IBD和其他炎症相关疾病（包括癌症）治疗的概念性新策略。
IQ motif-containing GTPase-activating protein 2 (IQGAP2) is a multidomain scaffolding protein that plays a role in cytoskeleton regulation by juxtaposing Rho GTPase and Ca2+/calmodulin signals. While IQGAP2 suppresses tumorigenesis in liver, its role in pathophysiology of the gastrointestinal tract remains unexplored. Here we report that IQGAP2 is required for the inflammatory response in colon. Mice lacking Iqgap2 gene (Iqgap2-/- mice) were resistant to chemically-induced colitis. Unlike wild-type controls, Iqgap2-/- mice treated with 3% dextran sulfate sodium (DSS) in water for 13 days displayed no injury to colonic epithelium. Mechanistically, resistance to colitis was associated with suppression of colonic NF-κB signaling and IL-6 synthesis, along with diminished neutrophil and macrophage production and recruitment in Iqgap2-/- mice. Finally, alterations in IQGAP2 expression were found in colons of patients with inflammatory bowel disease (IBD). Our findings indicate that IQGAP2 promotes inflammatory response at two distinct levels; locally, in colonic epithelium through TLR4/NF-κB signaling pathway, and systemically, via control of maturation and recruitment of myeloid immune cells. This work identifies a novel mechanism of colonic inflammation mediated by signal transducing scaffolding protein IQGAP2. IQGAP2 domain-specific blocking agents may represent a conceptually novel strategy for therapy of IBD and other inflammation-associated disorders, including cancer.
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