补体 C1q 激活经典 Wnt 信号通路并促进与衰老相关的表型。
Complement C1q activates canonical Wnt signaling and promotes aging-related phenotypes.
机构信息
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Japan.
出版信息
Cell. 2012 Jun 8;149(6):1298-313. doi: 10.1016/j.cell.2012.03.047.
Abstract
Wnt signaling plays critical roles in development of various organs and pathogenesis of many diseases, and augmented Wnt signaling has recently been implicated in mammalian aging and aging-related phenotypes. We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice, but not in those of C1qa-deficient mice. C1q activates canonical Wnt signaling by binding to Frizzled receptors and subsequently inducing C1s-dependent cleavage of the ectodomain of Wnt coreceptor low-density lipoprotein receptor-related protein 6. Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption. Our findings therefore suggest the unexpected role of complement C1q in Wnt signal transduction and modulation of mammalian aging.
摘要
Wnt 信号通路在多种器官的发育和许多疾病的发病机制中起着关键作用，最近有研究表明增强的 Wnt 信号通路与哺乳动物衰老和与衰老相关的表型有关。我们在此报告补体 C1q 可激活经典 Wnt 信号通路，并促进与衰老相关的组织再生能力下降。随着年龄的增长，血清 C1q 浓度增加，并且在血清和野生型小鼠的多种组织中，Wnt 信号通路的活性在衰老过程中增强，但在 C1qa 缺陷型小鼠中则没有。C1q 通过与 Frizzled 受体结合并随后诱导 Wnt 共受体低密度脂蛋白受体相关蛋白 6 的胞外结构域的 C1s 依赖性裂解来激活经典 Wnt 信号通路。外源性 C1q 处理可抑制年轻小鼠的骨骼肌再生，而 C1s 抑制或 C1qa 基因缺失可恢复与衰老相关的肌肉再生损伤。因此，我们的研究结果表明补体 C1q 在 Wnt 信号转导和调节哺乳动物衰老中具有意想不到的作用。
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