Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA 94158, USA.
State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
Sci Signal. 2018 Oct 2;11(550):eaat0138. doi: 10.1126/scisignal.aat0138.
Inadequate tissue oxygen, or hypoxia, is a central concept in the pathophysiology of ischemic disorders and cancer. Hypoxia promotes extracellular matrix (ECM) remodeling, cellular metabolic adaptation, and cancer cell metastasis. To discover new pathways through which cells respond to hypoxia, we performed a large-scale forward genetic screen in and identified a previously uncharacterized receptor tyrosine kinase named HIR-1. Loss of function in phenocopied the impaired ECM integrity associated with hypoxia or deficiency in the oxygen-dependent dual oxidase, heme peroxidases, or cuticular collagens involved in ECM homeostasis. Genetic suppressor screens identified NHR-49 and MDT-15 as transcriptional regulators downstream of HIR-1. Furthermore, mutants showed defects in adapting to and recovering from prolonged severe hypoxia. We propose that HIR-1 coordinates hypoxia-inducible factor-independent responses to hypoxia and hypoxia-associated ECM remodeling through mechanisms that are likely conserved in other organisms.
组织缺氧或缺氧是缺血性疾病和癌症病理生理学的核心概念。缺氧可促进细胞外基质 (ECM) 的重塑、细胞代谢适应和癌细胞转移。为了发现细胞对缺氧反应的新途径，我们在 中进行了大规模正向遗传筛选，并鉴定出一种以前未被表征的受体酪氨酸激酶，命名为 HIR-1。 的功能丧失与与缺氧相关的细胞外基质完整性受损或涉及细胞外基质稳态的氧依赖性双氧化酶、血红素过氧化物酶或表皮胶原缺陷表型相似。遗传抑制筛选鉴定出 NHR-49 和 MDT-15 是 HIR-1 的下游转录调节剂。此外， 突变体在适应和从长期严重缺氧中恢复方面表现出缺陷。我们提出， HIR-1 通过可能在其他生物体中保守的机制协调缺氧诱导因子非依赖性对缺氧的反应和缺氧相关的细胞外基质重塑。
