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HSP90 inhibitors stimulate DNAJB4 protein expression through a mechanism involving N6-methyladenosine

Author

Listed:
  • Weili Miao

    (University of California Riverside)

  • Lin Li

    (University of California Riverside)

  • Yonghui Zhao

    (University of California Riverside
    Shenzhen University)

  • Xiaoxia Dai

    (University of California Riverside)

  • Xuemei Chen

    (University of California Riverside)

  • Yinsheng Wang

    (University of California Riverside)

Abstract

Small-molecule inhibitors for the 90-kDa heat shock protein (HSP90) have been extensively exploited in preclinical studies for the therapeutic interventions of human diseases accompanied with proteotoxic stress. By using an unbiased quantitative proteomic method, we uncover that treatment with three HSP90 inhibitors results in elevated expression of a large number of heat shock proteins. We also demonstrate that the HSP90 inhibitor-mediated increase in expression of DNAJB4 protein occurs partly through an epitranscriptomic mechanism, and is substantially modulated by the writer, eraser, and reader proteins of N6-methyladenosine (m6A). Furthermore, exposure to ganetespib leads to elevated modification levels at m6A motif sites in the 5′-UTR of DNAJB4 mRNA, and the methylation at adenosine 114 site in the 5′-UTR promotes the translation of the reporter gene mRNA. This m6A-mediated mechanism is also at play upon heat shock treatment. Cumulatively, we unveil that HSP90 inhibitors stimulate the translation of DNAJB4 through an epitranscriptomic mechanism.

Suggested Citation

  • Weili Miao & Lin Li & Yonghui Zhao & Xiaoxia Dai & Xuemei Chen & Yinsheng Wang, 2019. "HSP90 inhibitors stimulate DNAJB4 protein expression through a mechanism involving N6-methyladenosine," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11552-8
    DOI: 10.1038/s41467-019-11552-8
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    Cited by:

    1. Kaushik Bhattacharya & Samarpan Maiti & Szabolcs Zahoran & Lorenz Weidenauer & Dina Hany & Diana Wider & Lilia Bernasconi & Manfredo Quadroni & Martine Collart & Didier Picard, 2022. "Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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