University of Oulu

Mennerich, D., Kubaichuk, K., Raza, G. S., Fuhrmann, D. C., Herzig, K.-H., Brüne, B., & Kietzmann, T. (2022). ER-stress promotes VHL-independent degradation of hypoxia-inducible factors via FBXW1A/βTrCP. Redox Biology, 50, 102243.

ER-stress promotes VHL-independent degradation of hypoxia-inducible factors via FBXW1A/βTrCP

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Author: Mennerich, Daniela1; Kubaichuk, Kateryna1; Raza, Ghulam S.2;
Organizations: 1Faculty of Biochemistry and Molecular Medicine, and Biocenter Oulu, University of Oulu, FI-90014, Oulu, Finland
2Research Unit of Biomedicine, and Biocenter Oulu, Oulu University Hospital and Medical Research Center, FI-90014, Oulu, Finland
3Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, D-60590, Frankfurt, Germany
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 9.7 MB)
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Language: English
Published: Elsevier, 2022
Publish Date: 2022-08-09


Metabolic adaptation and signal integration in response to hypoxic conditions is mainly regulated by hypoxia-inducible factors (HIFs). At the same time, hypoxia induces ROS formation and activates the unfolded protein response (UPR), indicative of endoplasmic reticulum (ER) stress. However, whether ER stress would affect the hypoxia response remains ill-defined. Here we report that feeding mice a high fat diet causes ER stress and attenuates the response to hypoxia. Mechanistically, ER stress promotes HIF-1α and HIF-2α degradation independent of ROS, Ca²⁺, and the von Hippel-Lindau (VHL) pathway, involving GSK3β and the ubiquitin ligase FBXW1A/βTrCP. Thereby, we reveal a previously unknown function of the GSK3β/HIFα/βTrCP1 axis in ER homeostasis and demonstrate that inhibition of the HIF-1 and HIF-2 response and genetic deficiency of GSK3β affects proliferation, migration, and sensitizes cells for ER stress promoted apoptosis. Vice versa, we show that hypoxia affects the ER stress response mainly through the PERK-arm of the UPR. Overall, we discovered previously unrecognized links between the HIF pathway and the ER stress response and uncovered an essential survival pathway for cells under ER stress.

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Series: Redox biology
ISSN: 2213-2317
ISSN-E: 2213-2317
ISSN-L: 2213-2317
Volume: 50
Article number: 102243
DOI: 10.1016/j.redox.2022.102243
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: This work was supported by the Academy of Finland SA296027, the Jane and Aatos Erkko Foundation 210031, the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, and Biocenter Oulu as a member of Biocenter Finland.
Academy of Finland Grant Number: 296027
Detailed Information: 296027 (Academy of Finland Funding decision)
Copyright information: © 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license.