Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Biopolis, 41500, Larissa, Greece.
Institute of Bioinnovation, BSRC "Alexander Fleming,", Vari, 16672, Greece.
Biochem Biophys Res Commun. 2021 Jun 11;557:143-150. doi: 10.1016/j.bbrc.2021.03.176. Epub 2021 Apr 14.
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.
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。
