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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Determination of HIF-1α degradation pathways via modulation of the propionyl mark

  • Kwanyoung Jeong (School of Pharmacy, Sungkyunkwan University) ;
  • Jinmi Choi (School of Pharmacy, Sungkyunkwan University) ;
  • Ahrum Choi (School of Pharmacy, Sungkyunkwan University) ;
  • Joohee Shim (School of Pharmacy, Sungkyunkwan University) ;
  • Young Ah Kim (Department of Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science, Seoul National University College of Medicine) ;
  • Changseok Oh (School of Pharmacy, Sungkyunkwan University) ;
  • Hong-Duk Youn (Department of Biomedical Sciences, Stochastic Stemness Research Center, Seoul National University College of Medicine) ;
  • Eun-Jung Cho (School of Pharmacy, Sungkyunkwan University)
  • Received : 2022.11.18
  • Accepted : 2023.02.09
  • Published : 2023.04.30
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Abstract

The hypoxia-inducible factor-1α (HIF-1α) is a key regulator of hypoxic stress under physiological and pathological conditions. HIF-1α protein stability is tightly regulated by the ubiquitin-proteasome system (UPS) and autophagy in normoxia, hypoxia, and the tumor environment to mediate the hypoxic response. However, the mechanisms of how the UPS and autophagy interplay for HIF-1α proteostasis remain unclear. Here, we found a HIF-1α species propionylated at lysine (K) 709 by p300/CREB binding protein (CBP). HIF-1α stability and the choice of degradation pathway were affected by HIF-1α propionylation. K709-propionylation prevented HIF-1α from degradation through the UPS, while activated chaperon-mediated autophagy (CMA) induced the degradation of propionylated and nonpropionylated HIF-1α. CMA contributed to HIF-1α degradation in both normoxia and hypoxia. Furthermore, the pan-cancer analysis showed that CMA had a significant positive correlation with the hypoxic signatures, whereas SIRT1, responsible for K709-depropionylation correlated negatively with them. Altogether, our results revealed a novel mechanism of HIF-1α distribution into two different degradation pathways.

Keywords

Acknowledgement

This work was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) (NRF-2022R1A2C2003505, 2021R1F1A1049941, and NRF-2019R1A5A2027340 to E.-J.C., NRF-2022R1C1C2005612 to J.C., and NRF2022R1A5A102641311 to H.-D.Y.).

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