CaMKII-mediated Beclin 1 phosphorylation regulates autophagy that promotes degradation of Id and neuroblastoma cell differentiation.
CaMKII-mediated Beclin 1 phosphorylation regulates autophagy that promotes degradation of Id and neuroblastoma cell differentiation.
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CaMKII 介导的 Beclin 1 磷酸化调节自噬，促进 Id 降解和神经母细胞瘤细胞分化
DOI：
10.1038/s41467-017-01272-2
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发表时间：
2017-10-27
影响因子：
16.6
通讯作者：
Zhu XF
中科院分区：
文献类型：
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作者：
Li X;Wu XQ;Deng R;Li DD;Tang J;Chen WD;Chen JH;Ji J;Jiao L;Jiang S;Yang F;Feng GK;Senthilkumar R;Yue F;Zhang HL;Wu RY;Yu Y;Xu XL;Mai J;Li ZL;Peng XD;Huang Y;Huang X;Ma NF;Tao Q;Zeng YX;Zhu XF
自噬是一种将细胞组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知之甚少。在这里，我们表明，CaMKII可以直接磷酸化Beclin 1的Ser 90，以促进K63连接的泛素化Beclin 1和自噬的激活。同时，CaMK Ⅱ还可以通过催化分化抑制因子1/2（Id-1/2）的磷酸化和募集TRAF-6来促进K63连接的泛素化。然后，泛素化的Id-1/Id-2可以与p62结合并被转运到自体溶酶体进行降解。Id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，通过自噬降解的Id蛋白可以调节细胞分化。这表明靶向CaMK II和调节Id的自噬降解可能是诱导神经母细胞瘤细胞分化的有效治疗策略。
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.