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

Semi Lim, Hye Young Cho, Dae Gyu Kim, Younah Roh, Se Young Son, Ameeq Ul Mushtaq, Minkyoung Kim, Deepak Bhattarai, Aneesh Sivaraman, Youngjin Lee, Jihye Lee, Won Suk Yang, Hoi Kyoung Kim, Myung Hee Kim, Kyeong Lee, Young Ho Jeon, Sunghoon Kim

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)31-41
Number of pages11
JournalNature Chemical Biology
Volume16
Issue number1
DOIs
Publication statusPublished - 2020 Jan 1

Bibliographical note

Funding Information:
This work was supported by the Global Frontier Project grant (no. NRF-M3A6A4-2010-0029785) and the IMRCTR grant (no. NRF-2018R1A5A2023127) of the National Research Foundation funded by the Ministry of Science and ICT of Korea. We thank T. Otomo of The Scripps Research Institute for helpful discussions. X-ray diffraction data were collected at Pohang Accelerator Laboratory beamlines 5C, 7A and 11C and Photon Factory beamline 1A. We used the NMR instruments of the Protein Structure Group at the Korea Basic Science Institute.

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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