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

Weili Miao, Lin Li, Yonghui Zhao, Xiaoxia Dai, Xuemei Chen and Yinsheng Wang ()
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Weili Miao: University of California Riverside
Lin Li: University of California Riverside
Yonghui Zhao: University of California Riverside
Xiaoxia Dai: University of California Riverside
Xuemei Chen: University of California Riverside
Yinsheng Wang: University of California Riverside

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11552-8

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