Targeting the interaction of AIMP2-DX2 with HSP70 suppresses cancer development

• Published in: Nature chemical biology Vol. 16; no. 1; pp. 31 - 41
• Main Authors: Lim, Semi, Cho, Hye Young, Kim, Dae Gyu, Roh, Younah, Son, Se-Young, Mushtaq, Ameeq Ul, Kim, Minkyoung, Bhattarai, Deepak, Sivaraman, Aneesh, Lee, Youngjin, Lee, Jihye, Yang, Won Suk, Kim, Hoi Kyoung, Kim, Myung Hee, Lee, Kyeong, Jeon, Young Ho, Kim, Sunghoon
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2020; Nature Publishing Group
• Subjects: 631/45/535/1266; 631/45/535/878; 631/67/1059; 631/92/613; Alternative Splicing; Animals; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Cancer; Cell Biology; Cell Line, Tumor; Cell Transformation, Neoplastic; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Crystallography; Crystallography, X-Ray; Disease Progression; Female; Gene Expression Regulation, Neoplastic; HEK293 Cells; HSP70 Heat-Shock Proteins - metabolism; Hsp70 protein; Humans; Lung cancer; Lung Neoplasms - metabolism; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred BALB C; Nuclear Proteins - metabolism; Protein Binding; Protein Interaction Mapping; Protein Multimerization; Surface Plasmon Resonance; Ubiquitin; Ubiquitin - chemistry
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/s41589-019-0415-2

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 Siah1-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. The cellular stability of an oncogenic factor, AIMP2-DX2, is increased via association with HSP70. Interference with this interaction by a small-molecule compound promotes ubiquitin-mediated degradation of AIMP2-DX2 and reduces cancer cell growth.