新型 HIF-2α 与 Reptin52 的相互作用会损害 HIF-2 的转录活性和 EPO 的分泌。

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

机构信息

Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Biopolis, 41500, Larissa, Greece.

Institute of Bioinnovation, BSRC "Alexander Fleming,", Vari, 16672, Greece.

出版信息

Biochem Biophys Res Commun. 2021 Jun 11;557:143-150. doi: 10.1016/j.bbrc.2021.03.176. Epub 2021 Apr 14.

DOI:10.1016/j.bbrc.2021.03.176

PMID:33865222

Abstract

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-2α phosphorylation by ERK1/2 that impairs its CRM1-mediated nuclear export. Herein, we reveal a novel interaction of HIF-2α with Reptin52, a multifunctional protein involved in cellular functions orchestrated both in the nucleus and the cytoplasm. HIF-2α 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-2α 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.

摘要

缺氧诱导因子 2 (HIF-2) 对于细胞对缺氧的反应至关重要，在红细胞生成、血管生成、组织侵袭和转移中发挥重要作用，因此成为一个重要的治疗靶点。最大程度的 HIF-2 转录激活需要 ERK1/2 对 HIF-2α 的磷酸化，这会损害其 CRM1 介导的核输出。在此，我们揭示了 HIF-2α 与 Reptin52 的一种新相互作用，Reptin52 是一种多功能蛋白，参与核内和细胞质中协调的细胞功能。HIF-2α 和 Reptin52 相互作用于核和细胞质部分，但 ERK1/2 通路失活似乎有利于它们在细胞质中的关联。值得注意的是，我们证明 Reptin52 通过非经典的 PHD-VHL-蛋白酶体独立机制，降低 HIF-2α 的稳定性，从而减少缺氧下 EPO 的分泌，降低 HIF-2 的转录活性。这种相互作用代表了一种新的 HIF-2 微调机制，允许不同的 HIF1/2 同工型的调节。