Targeting the interaction of AIMP2-DX2 with HSP70 suppresses cancer development
Targeting the interaction of AIMP2-DX2 with HSP70 suppresses cancer development
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DOI：
10.1038/s41589-019-0415-2
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发表时间：
2020-01-01
影响因子：
14.8
通讯作者：
Kim, Sunghoon
中科院分区：
文献类型：
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作者：
Lim, Semi;Cho, Hye Young;Kim, Sunghoon
缺乏外显子2的致瘤因子AIMP2 （AIMP2- dx2）在许多癌症中经常上调。然而，其细胞水平是如何确定的尚不清楚。在这里，我们报道热休克蛋白HSP70是AIMP2-DX2水平的关键决定因素。通过相互作用分析确定了这两个因素的相互作用，并通过x射线晶体学和核磁共振分析确定了其结构。HSP70通过底物结合域识别AIMP2-DX2的氨基末端柔性区和谷胱甘肽s -转移酶结构域，从而阻断AIMP2-DX2的siahl依赖性泛素化。HSP70进一步增强了aimp2 - dx2在体内诱导的细胞转化和肿瘤进展。在多种肺癌细胞系和患者组织中，HSP70与AIMP2-DX2水平呈正相关。体外和体内化学干预AIMP2-DX2-HSP70相互作用抑制癌细胞生长。因此，这项工作证明了AIMP2-DX2和HSP70之间的相互作用在肿瘤进展中的重要性及其对癌症的治疗潜力。
A tumorigenic factor, AIMP2 lacking exon 2 (AIMP2-DX2), is often upregulated in many cancers. However, how its cellular level is determined is not understood. Here, we report heat-shock protein HSP70 as a critical determinant for the level of AIMP2-DX2. Interaction of the two factors was identified by interactome analysis and structurally determined by X-ray crystallography and NMR analyses. HSP70 recognizes the amino (N)-terminal flexible region, as well as the glutathione S-transferase domain of AIMP2-DX2, via its substrate-binding domain, thus blocking the Siahl-dependent ubiquitination of AIMP2-DX2. AIMP2-DX2-induced cell transformation and cancer progression in vivo was further augmented by HSP70. A positive correlation between HSP70 and AIMP2-DX2 levels was shown in various lung cancer cell lines and patient tissues. Chemical intervention in the AIMP2-DX2-HSP70 interaction suppressed cancer cell growth in vitro and in vivo. Thus, this work demonstrates the importance of the interaction between AIMP2-DX2 and HSP70 on tumor progression and its therapeutic potential against cancer.