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 Caenorhabditis elegans and identified a previously uncharacterized receptor tyrosine kinase named HIR-1. Loss of function in hir-1 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, hir-1 mutants showed defects in adapting to and recovering from prolonged severe hypoxia. We propose that C. elegans HIR-1 coordinates hypoxia-inducible factor–independent responses to hypoxia and hypoxia-associated ECM remodeling through mechanisms that are likely conserved in other organisms.

组织氧不足或缺氧是缺血性疾病和癌症的病理生理学的中心概念。低氧促进细胞外基质（ECM）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，我们在秀丽隐杆线虫中进行了大规模的前向遗传筛选，并鉴定了一种以前未鉴定的受体酪氨酸激酶，称为HIR-1。在功能丧失HIR-1表型模拟与低氧或不足中的氧依赖性双氧化酶，过氧化物酶的血红素，或参与ECM稳态表皮胶原相关联的ECM受损完整性。遗传抑制物筛选确定NHR-49和MDT-15为HIR-1下游的转录调节因子。此外，hir-1突变体显示出在长期严重缺氧适应和恢复中的缺陷。我们建议秀丽隐杆线虫HIR-1通过可能在其他生物体中保守的机制来协调对低氧和与低氧相关的ECM重塑的低氧诱导因子非依赖性反应。