Intracellular complement C5a/C5aR1 stabilizes β-catenin to promote colorectal tumorigenesis
Intracellular complement C5a/C5aR1 stabilizes β-catenin to promote colorectal tumorigenesis
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细胞内补体 C5a/C5aR1 稳定 β-连环蛋白以促进结直肠肿瘤发生
DOI：
10.1016/j.celrep.2022.110851
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发表时间：
2022-05-31
期刊：
影响因子：
8.8
通讯作者：
Hu, Weiguo
中科院分区：
文献类型：
--
作者：
Ding, Peipei;Xu, Yanqing;Hu, Weiguo
补体不仅在细胞外环境中起作用，而且在细胞内环境中也起作用。然而，人们对补体激活在肿瘤细胞中的作用知之甚少。在这里，我们报道了细胞内的C5被组织蛋白酶D(CTSD)裂解，在结肠癌细胞的溶酶体和内体中产生C5a。在C5a刺激下，细胞内的C5aR1与KCTD5/cullin3/Roc-1和β-catenin形成一个复合体，促进β-catenin的多泛素化从K48转换为K63，从而增强了β-catenin的稳定性。C5aR1的基因缺失或药物阻断至少通过破坏β-连环蛋白的稳定来显着阻止结直肠肿瘤的发生。在人类结直肠癌标本中，C5aR1、C5a和CTSD的高水平与β-catenin水平升高和预后不良密切相关，重要的是，细胞内C5a/C5aR1介导的β-catenin稳定也普遍存在于其他类型的细胞中，我们共同确定了β-catenin激活的机制，并为肿瘤的预防和治疗提供了潜在的靶点。
Complement is operative in not only the extracellular but also the intracellular milieu. However, little is known about the role of complement activation inside tumor cells. Here, we report that intracellular C5 is cleaved by cathepsin D (CTSD) to produce C5a in lysosomes and endosomes of colonic cancer cells. After stimulation by C5a, intracellular C5aR1 assembles a complex with KCTD5/cullin3/Roc-1 and beta-catenin to promote the switch of polyubiquitination of beta-catenin from K48 to K63, which enhances beta-catenin stability. Genetic loss or pharmacological blockade of C5aR1 dramatically impedes colorectal tumorigenesis at least by destabilizing beta-catenin. In human colorectal cancer specimens, high levels of C5aR1, C5a, and CTSD are closely correlated with elevated beta-catenin levels and a poor prognosis, Importantly, intracellular C5a/C5aR1-mediated beta-catenin stabilization is also observed ubiquitously in other cell types, Collectively, we identify a machinery for beta-catenin activation and provide a potential target for tumor prevention and treatment.