1] Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H8L6 [2] Leibniz Institute for Age Research, Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07445 Jena, Germany.
Nat Commun. 2013;4:2869. doi: 10.1038/ncomms3869.
Wnt signaling has essential roles during embryonic development and tissue homoeostasis. Wnt proteins are post-translationally modified and the attachment of a palmitate moiety at two conserved residues is believed to be a prerequisite for the secretion and function of Wnt proteins. Here we demonstrate that a mammalian Wnt protein can be fully functional without palmitoylation. We generate a truncated Wnt7a variant, consisting of the C-terminal 137 amino acids lacking the conserved palmitoylation sites and show that it retains full biological activity in skeletal muscle. This includes binding to and signaling through its receptor Fzd7 to stimulate symmetric expansion of satellite stem cells by activating the planar-cell polarity pathway and inducing myofibre hypertrophy by signaling through the AKT/mTOR pathway. Furthermore, this truncated Wnt7a shows enhanced secretion and dispersion compared with the full-length protein. Together, these findings open important new avenues for the development of Wnt7a as a treatment for muscle-wasting diseases and have broad implications for the therapeutic use of Wnts as biologics.
Wnt 信号在胚胎发育和组织稳态中具有重要作用。Wnt 蛋白在翻译后被修饰，并且两个保守残基上的棕榈酸部分的附着被认为是 Wnt 蛋白分泌和功能的先决条件。在这里，我们证明哺乳动物 Wnt 蛋白可以在没有棕榈酰化的情况下完全发挥功能。我们生成了一种截断的 Wnt7a 变体，由缺乏保守棕榈酰化位点的 C 末端 137 个氨基酸组成，并表明它在骨骼肌中保留了完整的生物学活性。这包括通过与其受体 Fzd7 结合并通过激活平面细胞极性途径来刺激卫星干细胞的对称扩增，并通过 AKT/mTOR 途径发出信号诱导肌纤维肥大。此外，与全长蛋白相比，这种截断的 Wnt7a 显示出增强的分泌和分散。总之，这些发现为将 Wnt7a 开发为治疗肌肉消耗性疾病的方法开辟了重要的新途径，并为 Wnt 作为生物制剂的治疗用途提供了广泛的影响。
