Institute of Physiology, University Duisburg-Essen, Essen, Germany.
Mol Cell Biol. 2023;43(4):174-183. doi: 10.1080/10985549.2023.2198931. Epub 2023 Apr 19.
The ability of cells to communicate with their surrounding is a prerequisite for essential processes such as proliferation, apoptosis, migration, and differentiation. To this purpose, primary cilia serve as antennae-like structures on the surface of most mammalian cell types. Cilia allow signaling via hedgehog, Wnt or TGF-beta pathways. Their length, in part controlled by the activity of intraflagellar transport (IFT), is a parameter for adequate function of primary cilia. Here we show, in murine neuronal cells, that intraflagellar transport protein 88 homolog (IFT88) directly interacts with the hypoxia-inducible factor-2α (HIF-2α), hitherto known as an oxygen-regulated transcription factor. Furthermore, HIF-2α accumulates in the ciliary axoneme and promotes ciliary elongation under hypoxia. Loss of HIF-2α affected ciliary signaling in neuronal cells by decreasing transcription of and . Targets of the MEK/ERK signaling pathway, such as and , were significantly decreased. Our results suggest that HIF-2α influences ciliary signaling by interacting with IFT88 under hypoxic conditions. This implies an unexpected and far more extensive function of HIF-2α than described before.
细胞与周围环境进行通讯的能力是增殖、凋亡、迁移和分化等基本过程的前提。为此,初级纤毛作为大多数哺乳动物细胞类型表面的类似天线的结构。纤毛允许通过 hedgehog、Wnt 或 TGF-β 途径进行信号传递。它们的长度部分受内鞭毛运输(IFT)的活性控制,是初级纤毛正常功能的一个参数。在这里,我们在鼠神经元细胞中表明,内鞭毛运输蛋白 88 同源物(IFT88)直接与缺氧诱导因子-2α(HIF-2α)相互作用,HIF-2α 以前是一种氧调节转录因子。此外,HIF-2α 在纤毛轴丝中积累,并在缺氧下促进纤毛伸长。HIF-2α 的缺失通过降低 和 的转录,影响神经元细胞中的纤毛信号。MEK/ERK 信号通路的靶标,如 和 ,显著减少。我们的结果表明,HIF-2α 在缺氧条件下通过与 IFT88 相互作用影响纤毛信号。这意味着 HIF-2α 的作用比以前描述的更为广泛和出乎意料。