Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
J Cell Biol. 2014 Mar 3;204(5):747-58. doi: 10.1083/jcb.201304167. Epub 2014 Feb 24.
Activation of the PI3K-Akt-FoxO pathway induces cell growth, whereas its inhibition reduces cell survival and, in muscle, causes atrophy. Here, we report a novel mechanism that suppresses PI3K-Akt-FoxO signaling. Although skeletal muscle lacks desmosomes, it contains multiple desmosomal components, including plakoglobin. In normal muscle plakoglobin binds the insulin receptor and PI3K subunit p85 and promotes PI3K-Akt-FoxO signaling. During atrophy, however, its interaction with PI3K-p85 is reduced by the ubiquitin ligase Trim32 (tripartite motif containing protein 32). Inhibition of Trim32 enhanced plakoglobin binding to PI3K-p85 and promoted PI3K-Akt-FoxO signaling. Surprisingly, plakoglobin overexpression alone enhanced PI3K-Akt-FoxO signaling. Furthermore, Trim32 inhibition in normal muscle increased PI3K-Akt-FoxO signaling, enhanced glucose uptake, and induced fiber growth, whereas plakoglobin down-regulation reduced PI3K-Akt-FoxO signaling, decreased glucose uptake, and caused atrophy. Thus, by promoting plakoglobin-PI3K dissociation, Trim32 reduces PI3K-Akt-FoxO signaling in normal and atrophying muscle. This mechanism probably contributes to insulin resistance during fasting and catabolic diseases and perhaps to the myopathies and cardiomyopathies seen with Trim32 and plakoglobin mutations.
PI3K-Akt-FoxO 通路的激活可诱导细胞生长，而其抑制则降低细胞存活，在肌肉中则导致萎缩。在这里，我们报告了一种抑制 PI3K-Akt-FoxO 信号的新机制。尽管骨骼肌缺乏桥粒，但它含有多种桥粒成分，包括桥粒斑蛋白。在正常肌肉中，桥粒斑蛋白与胰岛素受体和 PI3K 亚基 p85 结合，并促进 PI3K-Akt-FoxO 信号。然而，在萎缩过程中，其与 PI3K-p85 的相互作用被泛素连接酶 Trim32（三结构域蛋白 32）减少。Trim32 的抑制增强了桥粒斑蛋白与 PI3K-p85 的结合，并促进了 PI3K-Akt-FoxO 信号。令人惊讶的是，桥粒斑蛋白的过表达本身就增强了 PI3K-Akt-FoxO 信号。此外，正常肌肉中 Trim32 的抑制增加了 PI3K-Akt-FoxO 信号，增强了葡萄糖摄取，并诱导纤维生长，而桥粒斑蛋白的下调则降低了 PI3K-Akt-FoxO 信号，减少了葡萄糖摄取，并导致萎缩。因此，通过促进桥粒斑蛋白与 PI3K 的解离，Trim32 减少了正常和萎缩肌肉中的 PI3K-Akt-FoxO 信号。这种机制可能有助于在禁食和分解代谢疾病期间的胰岛素抵抗，并且可能与 Trim32 和桥粒斑蛋白突变相关的肌肉病和心肌病有关。
