Laboratoire de Génomique Fonctionnelle et Myogenèse, UMR 866 DMEM, INRA UM II, Montpellier, France.
FEBS Lett. 2012 Feb 17;586(4):362-7. doi: 10.1016/j.febslet.2011.12.031. Epub 2012 Jan 11.
In skeletal muscle atrophy, upregulation and nuclear accumulation of the Ubiquitin E3 ligase MAFbx is essential for accelerated muscle protein loss, but the nuclear/cytoplasmic shuttling of MAFbx is undefined. Here we found that MAFbx contains two functional nuclear localization signals (NLS). Mutation or deletion of only one NLS induced cytoplasmic localization of MAFbx. We identified a non-classical NES located in the leucine charged domain (LCD) of MAFbx, which is leptomycin B insensitive. We demonstrated that mutation (L169Q) in LLXXL motif of LCD suppressed cytoplasmic retention of MAFbx. Nucleocytoplasmic shuttling of MAFbx represents a novel mechanism for targeting its substrates and its cytosolic partners in muscle atrophy.
在骨骼肌萎缩中，泛素 E3 连接酶 MAFbx 的上调和核积累对于加速肌肉蛋白损失是必不可少的，但 MAFbx 的核/细胞质穿梭尚未明确。在这里，我们发现 MAFbx 包含两个功能性核定位信号 (NLS)。仅一个 NLS 的突变或缺失会诱导 MAFbx 的细胞质定位。我们鉴定出一个位于 MAFbx 的亮氨酸带电荷域 (LCD)中的非经典核输出信号 (NES)，它对莱姆素 B 不敏感。我们证明，LCD 中 LLXXL 基序中的突变 (L169Q) 抑制了 MAFbx 的细胞质保留。MAFbx 的核质穿梭代表了一种将其底物及其在肌肉萎缩中的细胞质伴侣靶向的新机制。
