Novel HIF-2α interaction with Reptin52 impairs HIF-2 transcriptional activity and EPO secretion

Hypoxia-inducible factor 2 (HIF-2), is essential for cellular response to hypoxia and holds an important role in erythropoiesis, angiogenesis, tissue invasion and metastasis, thus, constituting an important therapeutic target. Maximal HIF-2 transcriptional activation requires HIF-2a phosphorylation by ERK1/2 that impairs its CRM1-mediated nuclear export. Herein, we reveal a novel interaction of HIF-2a with Reptin52, a multifunctional protein involved in cellular functions orchestrated both in the nucleus and the cytoplasm. HIF-2a and Reptin52 interact both in nuclear and cytoplasmic fractions, however, ERK1/2 pathway inactivation seems to favour their association in the cytoplasm. Notably, we demonstrate that Reptin52 reduces HIF-2 transcriptional activity, which results in decreased EPO secretion under hypoxia, by impairing HIF-2a stability via a non-canonical PHD-VHL-proteasome independent mechanism. This interaction represents a novel HIF-2 fine tuning mechanism that allows for distinct HIF1/2 isoforms regulation. (c) 2021 Elsevier Inc. All rights reserved.

Automated summary

Hypoxia-inducible factor 2 (HIF-2) plays a crucial role in cellular response to low oxygen levels and interacts with Reptin52 to affect cellular functions, primarily in the cytoplasm. This interaction can modulate HIF-2 transcriptional activity, leading to changes in EPO secretion and impacting physiological activities in the body.