NLRC3 is an inhibitory sensor of PI3K-mTOR pathways in cancer.
NLRC3 is an inhibitory sensor of PI3K-mTOR pathways in cancer.
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DOI：
10.1038/nature20597
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发表时间：
2016-12-22
期刊：
影响因子：
64.8
通讯作者：
Kanneganti TD
中科院分区：
文献类型：
--
作者：
Karki R;Man SM;Malireddi RKS;Kesavardhana S;Zhu Q;Burton AR;Sharma BR;Qi X;Pelletier S;Vogel P;Rosenstiel P;Kanneganti TD
核苷酸结合域，富含亮氨酸重复序列的蛋白(NLRs)属于细胞质感受器大家族，调节着一系列非常不同的生物学功能。NLRs有助于对传染病的免疫，但其功能活性的失调会导致炎症性疾病和自身免疫的发展。细胞质天然免疫感受器，包括NLR，是肠道内稳态的中央调节因子。NLRC3(也称为CLR16.2或NOD3)是NLR家族中一个特征较差的成员，在编码富含亮氨酸重复序列(LRR)和核苷酸结合结构域的基因的基因组筛选中被发现。与健康组织相比，编码NLRC3的基因在结直肠癌患者肿瘤组织中的表达显著降低，这突显了该传感器在癌症发生发展中的一种未知的潜在功能。在这里，我们发现缺乏NLRC3的小鼠对结肠炎和结直肠肿瘤具有超敏性。NLRC3在肠上皮细胞中的作用最为明显，它抑制mTOR信号通路的激活，抑制细胞增殖和干细胞衍生的有机体的形成。NLRC3与磷脂酰肌醇3-激酶(PI3Ks)相关，并阻断生长因子受体或TLR4结合后PI3K依赖的激酶AKT的激活。这些发现揭示了NLRC3作为mTOR通路抑制剂的关键作用，该通路介导了对结直肠癌的保护。
Nucleotide-binding domain, leucine-rich repeat containing proteins (NLRs) belong to a large family of cytoplasmic sensors which regulate an extraordinarily diverse range of biological functions. NLRs contribute to immunity against infectious diseases, however, dysregulation of their functional activity leads to the development of inflammatory diseases and autoimmunity . Cytoplasmic innate immune sensors, including NLRs, are central regulators of intestinal homeostasis . NLRC3 (also known as CLR16.2 or NOD3) is a poorly characterized member of the NLR family and was identified in a genomic screen of genes encoding proteins bearing leucine-rich repeats (LRRs) and nucleotide-binding domains . Expression of the gene encoding NLRC3 is drastically reduced in tumour tissues of patients with colorectal cancer compared with healthy tissues , highlighting an undefined potential function for this sensor in the development of cancer. Here, we found that mice lacking NLRC3 were hypersusceptible to colitis and colorectal tumorigenesis. The effect of NLRC3 was most dominant in enterocytes, where NLRC3 suppressed activation of the mTOR signalling pathways and inhibited cellular proliferation and stem-cell-derived organoid formation. NLRC3 associated with phosphoinositide 3-kinases (PI3Ks) and blocked activation of the PI3K–dependent kinase AKT following engagement of growth factor receptors or TLR4. These findings unveiled a key role for NLRC3 as an inhibitor of the mTOR pathways mediating protection against colorectal cancer.