Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma.,Nature Cell Biology

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Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma.
Nature Cell Biology ( IF 17.3 ) Pub Date : 2020-03-16 , DOI: 10.1038/s41556-020-0481-4
Tiffany Tsang _{1,

2} , Jessica M Posimo ₁ , Andrea A Gudiel ₁ , Michelle Cicchini ₁ , David M Feldser _{1,

3} , Donita C Brady _{1,

3}

Affiliation

Although the transition metal copper (Cu) is an essential nutrient that is conventionally viewed as a static cofactor within enzyme active sites, a non-traditional role for Cu as a modulator of kinase signalling is emerging. Here, we found that Cu is required for the activity of the autophagic kinases ULK1 and ULK2 (ULK1/2) through a direct Cu-ULK1/2 interaction. Genetic loss of the Cu transporter Ctr1 or mutations in ULK1 that disrupt the binding of Cu reduced ULK1/2-dependent signalling and the formation of autophagosome complexes. Increased levels of intracellular Cu are associated with starvation-induced autophagy and are sufficient to enhance ULK1 kinase activity and, in turn, autophagic flux. The growth and survival of lung tumours driven by KRASG12D is diminished in the absence of Ctr1, is dependent on ULK1 Cu binding and is associated with reduced levels of autophagy and signalling. These findings suggest a molecular basis for exploiting Cu-chelation therapy to prevent autophagy signalling to limit proliferation and improve patient survival in cancer.

中文翻译：

铜是自噬激酶ULK1 / 2驱动肺腺癌的重要调节剂。

尽管过渡金属铜（Cu）是一种必需营养素，通常被视为酶活性位点内的静态辅助因子，但铜作为激酶信号调节剂的非传统作用正在兴起。在这里，我们发现通过直接的Cu-ULK1 / 2相互作用，Cu对于自噬激酶ULK1和ULK2（ULK1 / 2）的活性是必需的。铜转运蛋白Ctr1的遗传损失或破坏铜结合的ULK1突变降低了ULK1 / 2依赖性信号传导和自噬体复合物的形成。细胞内铜水平的升高与饥饿诱导的自噬有关，并足以增强ULK1激酶活性，进而增强自噬通量。在缺少Ctr1的情况下，由KRASG12D驱动的肺肿瘤的生长和存活率降低，依赖于ULK1 Cu结合，并与自噬和信号转导水平降低有关。这些发现提示了开发铜螯合疗法以防止自噬信号转导限制增殖并改善癌症患者生存的分子基础。

更新日期：2020-04-24

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