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Inhibition of the ubiquitination of HSF1 by FBXW7 protects the intestine against ischemia–reperfusion injury

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Abstract

Epithelial apoptosis is an important factor in intestinal ischemia–reperfusion (I/R) injury. Heat shock factor 1 (HSF1) is a classical stress response factor that directly regulates the transcription of heat shock proteins (HSPs) under stress conditions. Although HSPs are involved in protecting the intestine against I/R, the mechanism whereby HSF1 is regulated in I/R is poorly understood. Here, we show that the ubiquitin ligase FBXW7 targets HSF1 for ubiquitination and degradation in intestinal I/R. In this study, we found that FBXW7 expression was upregulated at the transcriptional level in intestinal mucosae subjected to I/R. In Caco-2 and IEC-6 cells subjected to hypoxia/reoxygenation (H/R), a high FBXW7 level led to excessive HSF1 ubiquitination and degradation. FBXW7 knockdown attenuated HSF1 ubiquitination and downregulation and accelerated HSPB1 and HSP70 expression. In addition, FBXW7 deletion alleviated the apoptosis of intestinal epithelial cells, as evidenced by decreased activation of caspase-3 and caspase-9. The results suggest that FBXW7 suppression protects against intestinal I/R, at least partly through the HSF1/HSP pathway. These findings indicate that FBXW7 may be a potential therapeutic target for inhibiting intestinal mucosa apoptosis during intestinal I/R.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Grant Nos. 81671954 and 81372037 to Xiaofeng Tian and No. 81501699 to Feng Zhang).

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  1. Wenzhi Tan and Huanyu Zhao have contributed equally to this work.

Authors and Affiliations

  1. Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China

    Wenzhi Tan, Feng Zhang, Zhenlu Li, Dongcheng Feng, Yang Li, Wei Zhou, Liwei Liu & Xiaofeng Tian

  2. Department of Pharmacology, Dalian Medical University, Dalian, 116044, China

    Huanyu Zhao & Jihong Yao

  3. Department of General Surgery, Huizhou Municipal Central People’s Hospital, Huizhou, 516000, China

    Wenzhi Tan

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  1. Wenzhi Tan
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Contributions

XT, WT and JY designed the study. WT, HZ, LL and WZ performed the experiments. WT, FZ, YL, DF, ZL and JY analyzed and interpreted the data. XT, JY and FZ wrote and revised the manuscript. XT provided financial support. All authors reviewed and approved the manuscript.

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Correspondence to Jihong Yao or Xiaofeng Tian.

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Tan, W., Zhao, H., Zhang, F. et al. Inhibition of the ubiquitination of HSF1 by FBXW7 protects the intestine against ischemia–reperfusion injury. Apoptosis 23, 667–678 (2018). https://doi.org/10.1007/s10495-018-1484-5

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