State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, 510060, Guangzhou, China.
The 3rd Affiliated Hospital, Sun Yat-sen University, 510620, Guangzhou, China.
Nat Commun. 2017 Oct 27;8(1):1159. doi: 10.1038/s41467-017-01272-2.
Autophagy is a degradative pathway that delivers cellular components to the lysosome for degradation. The role of autophagy in cell differentiation is poorly understood. Here we show that CaMKII can directly phosphorylate Beclin 1 at Ser90 to promote K63-linked ubiquitination of Beclin 1 and activation of autophagy. Meanwhile, CaMKII can also promote K63-linked ubiquitination of inhibitor of differentiation 1/2 (Id-1/2) by catalyzing phosphorylation of Id proteins and recruiting TRAF-6. Ubiquitinated Id-1/Id-2 can then bind to p62 and be transported to autolysosomes for degradation. Id degradation promotes the differentiation of neuroblastoma cells and reduces the proportion of stem-like cells. Our study proposes a mechanism by which autophagic degradation of Id proteins can regulate cell differentiation. This suggests that targeting of CaMKII and the regulation of autophagic degradation of Id may be an effective therapeutic strategy to induce cell differentiation in neuroblastoma.
自噬是一种将细胞成分递送至溶酶体进行降解的降解途径。自噬在细胞分化中的作用尚不清楚。在这里，我们表明 CaMKII 可以直接在 Ser90 处磷酸化 Beclin 1，以促进 Beclin 1 的 K63 连接泛素化和自噬的激活。同时，CaMKII 还可以通过催化 Id 蛋白的磷酸化并募集 TRAF-6，促进分化抑制因子 1/2（Id-1/2）的 K63 连接泛素化。然后，泛素化的 Id-1/Id-2 可以与 p62 结合，并被转运到自噬溶酶体中进行降解。Id 的降解促进神经母细胞瘤细胞的分化，并降低干细胞样细胞的比例。我们的研究提出了一种机制，即 Id 蛋白的自噬性降解可以调节细胞分化。这表明靶向 CaMKII 和调节 Id 的自噬性降解可能是诱导神经母细胞瘤细胞分化的有效治疗策略。
