Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea.
Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
Cell. 2015 Apr 23;161(3):595-609. doi: 10.1016/j.cell.2015.03.011. Epub 2015 Apr 16.
Organisms must be able to respond to low oxygen in a number of homeostatic and pathological contexts. Regulation of hypoxic responses via the hypoxia-inducible factor (HIF) is well established, but evidence indicates that other, HIF-independent mechanisms are also involved. Here, we report a hypoxic response that depends on the accumulation of lactate, a metabolite whose production increases in hypoxic conditions. We find that the NDRG3 protein is degraded in a PHD2/VHL-dependent manner in normoxia but is protected from destruction by binding to lactate that accumulates under hypoxia. The stabilized NDRG3 protein binds c-Raf to mediate hypoxia-induced activation of Raf-ERK pathway, promoting angiogenesis and cell growth. Inhibiting cellular lactate production abolishes the NDRG3-mediated hypoxia responses. Our study, therefore, elucidates the molecular basis for lactate-induced hypoxia signaling, which can be exploited for the development of therapies targeting hypoxia-induced diseases.
在许多内稳态和病理情况下，生物体必须能够对低氧做出反应。通过缺氧诱导因子 (HIF) 调节低氧反应已经得到充分证实，但有证据表明，其他非 HIF 依赖的机制也参与其中。在这里，我们报告了一种依赖于乳酸积累的低氧反应，乳酸是一种代谢物，其在低氧条件下的产量增加。我们发现，NDRG3 蛋白在常氧条件下以 PHD2/VHL 依赖性方式降解，但通过与在低氧下积累的乳酸结合而免受破坏。稳定的 NDRG3 蛋白与 c-Raf 结合，介导缺氧诱导的 Raf-ERK 通路的激活，促进血管生成和细胞生长。抑制细胞内乳酸的产生会消除 NDRG3 介导的低氧反应。因此，我们的研究阐明了乳酸诱导的低氧信号的分子基础，这可用于开发针对低氧诱导疾病的治疗方法。
