TY  - JOUR
A1  - Mennerich, Daniela
A1  - Kubaichuk, Kateryna
A1  - Raza, Ghulam S.
A1  - Fuhrmann, Dominik Christian
A1  - Herzig, Karl-Heinz
A1  - Brüne, Bernhard
A1  - Kietzmann, Thomas
T1  - ER-stress promotes VHL-independent degradation of hypoxia-inducible factors via FBXW1A/βTrCP
T2  - Redox Biology
N2  - 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.
KW  - ER stress
KW  - HIF-1α
KW  - HIF-2α
KW  - Mild hypoxia
KW  - UPR
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/78438
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-784380
SN  - 2213-2317
VL  - 50
IS  - 102243
PB  - Elsevier
CY  - Amsterdam
ER  -