Distinct Phospholipase C-β Isozymes Mediate Lysophosphatidic Acid Receptor 1 Effects on Intestinal Epithelial Homeostasis and Wound Closure
Distinct Phospholipase C-β Isozymes Mediate Lysophosphatidic Acid Receptor 1 Effects on Intestinal Epithelial Homeostasis and Wound Closure
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DOI：
10.1128/mcb.00038-13
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发表时间：
2013-05-01
影响因子：
5.3
通讯作者：
Yun, C. Chris
中科院分区：
文献类型：
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作者：
Lee, Sei-Jung;Leoni, Giovanna;Yun, C. Chris
肠道上皮屏障的维持对于保护宿主免受恶劣管腔环境的侵袭是必要的。磷脂酶C-β(PLC-β)参与调控多种信号转导通路。然而，选择性PLC-β同工酶的生物学效应却鲜为人知。我们描述了新的发现，溶血磷脂酸(LPA)通过两个不同的途径调节PLC-β1和PLC-β2，促进肠上皮细胞(IEC)的增殖和迁移，从而促进伤口闭合和肠上皮屏障的恢复。LPA作用于LPA(1)受体，通过促进GαQ与PLC-β2的相互作用促进IEC的迁移。LPA诱导的细胞增殖依赖于PLC-β1，涉及GαQ移位到细胞核，在那里它与PLC-β1相互作用，诱导细胞周期进展。一项使用LPA1缺陷小鼠(Lpar1(-/-))的体内研究显示，增殖的IECs数量减少，并沿隐窝-腔轴迁移。此外，LPA以LPA(1)依赖的方式促进IECs的迁移和增殖，Lpar1(-/-)小鼠表现出需要细胞增殖和迁移的黏膜损伤修复缺陷。这些发现描绘了新的LPA(1)依赖的脂质信号，通过细胞内不同的PLC-βS的空间靶向促进粘膜创伤修复。
Maintenance of the epithelial barrier in the intestinal tract is necessary to protect the host from the hostile luminal environment. Phospholipase C-beta (PLC-beta) has been implicated to control myriad signaling cascades. However, the biological effects of selective PLC-beta isozymes are poorly understood. We describe novel findings that lysophosphatidic acid (LPA) regulates PLC-beta 1 and PLC-beta 2 via two distinct pathways to enhance intestinal epithelial cell (IEC) proliferation and migration that facilitate wound closure and recovery of the intestinal epithelial barrier. LPA acting on the LPA(1) receptor promotes IEC migration by facilitating the interaction of G alpha q with PLC-beta 2. LPA-induced cell proliferation is PLC-beta 1 dependent and involves translocation of G alpha q to the nucleus, where it interacts with PLC-beta 1 to induce cell cycle progression. An in vivo study using LPA1-deficient mice (Lpar1(-/-)) shows a decreased number of proliferating IECs and migration along the crypt-luminal axis. Additionally, LPA enhances migration and proliferation of IECs in an LPA(1)-dependent manner, and Lpar1(-/-) mice display defective mucosal wound repair that requires cell proliferation and migration. These findings delineate novel LPA(1)-dependent lipid signaling that facilitates mucosal wound repair via spatial targeting of distinct PLC-beta s within the cell.