HIR-1 Mediates Response to Hypoxia-Induced Extracellular Matrix Remodeling

Abstract

Inadequate tissue oxygen, or hypoxia, is a central concept in pathophysiology of ischemic disorders and cancer. Hypoxia promotes extracellular matrix (ECM) remodeling, cellular metabolic adaptation and metastasis. To determine how cells respond to hypoxia-induced ECM remodeling, we performed a large-scale forward genetic screen in C. elegans. We identified a previously uncharacterized receptor tyrosine kinase (RTK) named HIR-1 as a key mediator in a pathway that orchestrates transcriptional responses to hypoxia-induced ECM remodeling. Impaired ECM integrity caused by hypoxia or deficiency of the oxygen-dependent procollagen hydroxylases, heme peroxidases or cuticular collagens activates gene expression through inhibition of HIR-1. Genetic suppressor screens identified NHR-49 and MDT-15 as transcriptional regulators downstream of HIR-1. Cellular responses through HIR-1 maintain ECM homeostasis and promote animal adaptation to severe hypoxia. We propose that C. elegans HIR-1 defines an unprecedented type of RTK that mediates responses to hypoxia-induced ECM remodeling by mechanisms that are likely conserved in other organisms.