Regulation of colonic epithelial cell homeostasis by mTORC1
Regulation of colonic epithelial cell homeostasis by mTORC1
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DOI：
10.1038/s41598-020-70655-1
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发表时间：
2020-08-14
影响因子：
4.6
通讯作者：
Matozaki, Takashi
中科院分区：
文献类型：
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作者：
Kotani, Takenori;Setiawan, Jajar;Matozaki, Takashi
对于结肠上皮细胞(CECs)内环境平衡调节的重要细胞信号仍然知之甚少。哺乳动物雷帕霉素靶标复合体1(MTORC1)是一种含有丝氨酸-苏氨酸激酶MTO R的蛋白质复合体，它介导的信号转导是控制细胞增殖和自噬等各种外界刺激功能的基础。我们在这里表明，消融结节硬化症复合体2(TSC2)，mTORC1的负调控因子，特别是在小鼠肠上皮细胞中，导致mTORC1活性增加，以及CECs的增殖活性增加。TSC2条件基因敲除小鼠结肠组织中Lgr5阳性的结肠干细胞数量和Wnt靶基因的表达也明显减少。TSC2条件性基因敲除小鼠结肠中KAKt的激活性磷酸化和糖原合成酶K3β的抑制性磷酸化均显著降低。与对照组相比，TSC2 CKO组小鼠结肠类器官发育明显增强。最后，TSC2 CKO小鼠对葡聚糖硫酸钠诱导的结肠炎的易感性增加。因此，我们的结果提示，mTORC 1活性促进了CEC S细胞的增殖和WNT靶基因的表达，从而促进了结肠器官的发生和稳态。
Cell signaling important for homeostatic regulation of colonic epithelial cells (CECs) remains poorly understood. Mammalian target of rapamycin complex 1 (mTORC1), a protein complex that contains the serine-threonine kinase mTO R, mediates signaling that underlies the control of cellular functions such as proliferation and autophagy by various external stimuli. We here show that ablation of tuberous sclerosis complex 2 (Tsc2), a negative regulator of mTORC1, specifically in intestinal epithelial cells of mice resulted in increased activity of mTORC1 of, as well as increased proliferative activity of, CECs. Such Tsc2 ablation also reduced the population of Lgr5-positive colonic stem cells and the expression of Wnt target genes in CEC s. The stimulatory phosphorylation of the kinase Akt and inhibitory phosphorylation of glycogen synthase kinase 3 beta were both markedly decreased in the colon of the Tsc2 conditional knockout (CKO) mice. Development of colonic organoids with cryptlike structures was enhanced for Tsc2 CKO mice compared with control mice. Finally, Tsc2 CKO mice manifested increased susceptibility to dextran sulfate sodium-induced colitis. Our results thus suggest that mTORC1 activity promotes the proliferation of, as well as the expression of Wnt target genes in, CEC s and thereby contributes to colonic organogenesis and homeostasis.