HYPOXIA-INDUCIBLE FACTOR REGULATION OF INTESTINAL AUTOPHAGY

Abstract Inflammatory bowel disease (IBD) is a condition characterized by chronic, relapsing inflammation of the gastrointestinal (GI) tract. IBD is estimated to affect as many as 3.1 million Americans, incurring over $31 billion in economic costs annually. IBD has no cure, and current treatments are hampered by deficiencies such as gradual loss of efficacy and immunosuppression. The development of new IBD therapeutics is complicated by an incomplete understanding of IBD etiology, with no one genetic or environmental factor being solely responsible for disease causation. As such, there exists a clear need to better understand the pathophysiology of IBD to inform the development of improved IBD treatments. One factor previously implicated in intestinal pathology is the transcription factor family HIF (hypoxia-inducible factor). HIF guides the cellular response to diverse stressors, of which the response to low oxygen tensions (hypoxia) is best understood. The intestinal epithelium exists at a state of “physiologic hypoxia”, and past studies shown HIF to be protective in animal models of colitis. This protection is mediated through coordination of diverse cellular functions, including regulation of cellular energy homeostasis and potentiation of intestinal barrier function. Previous work by our group and others has implicated HIF in the regulation of autophagy in the intestinal epithelium. Autophagy, a highly conserved mechanism for clearance of cytosolic material, has also been shown to be genetically dysregulated in IBD. The targeting of intestinal autophagy via HIF signaling is an attractive avenue for treatment of IBD; however, the mechanism by which HIF regulates autophagy in the intestinal epithelium is not well understood. Using newly developed molecular tools, our group demonstrates here that hypoxia regulates autophagy in epithelial cells. We find that this regulation is dependent on HIF, yet activation of HIF alone (through HIF stabilizing compounds) is not sufficient to induce autophagy. We also observe a specific bias towards selective autophagy pathways as opposed to bulk/nonselective autophagy in the hypoxia-induced upregulation of autophagic flux. In summary, this work helps to uncover the molecular mechanisms by which HIF regulates autophagy in the intestinal epithelium and lays the foundation for the development of novel IBD therapeutics that leverage the HIF-autophagy axis. Figure 1:Regulation of autophagy by HIF. Stabilization of HIF-α subunits (e.g., by hypoxia) results in heterodimerization with HIF-1β/ARNT and transcription of autophagy genes, resulting in increased autophagic flux. Image made using BioRender.