What (H)IF isoform matters? A deubiquitinase can tune the hypoxic response

Abstract

Context-specific control mechanisms of hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha in tumors exposed to oxygen shortage remain incompletely understood. In this issue, Zhang et al (2022) identify a deubiquitinase that differentially stabilizes HIF-2alpha in stem-like glioblastoma cells, suggesting potential implications for regulation of the hypoxic response in a wide array of tissues and cancers.

Figure 1. Oxygen‐dependent regulation of HIF‐1alpha and HIF‐2alpha

(A) When oxygen is abundant, PHD1‐3‐mediated hydroxylation targets HIF‐1alpha and HIF‐2alpha for recognition by the VHL complex. VHL‐mediated ubiquitination in turn targets both HIF‐alpha isoforms for proteasomal degradation. FIH‐1‐mediated hydroxylation can further inhibit any HIF transcriptional activity in the presence of oxygen. (B) Zhang et al (2022) found that under hypoxic conditions, USP33 can deubiquitinate HIF‐2alpha specifically, thereby saving it from oxygen‐dependent degradation. In intermediately oxygenated tissues, HIF2alpha, but not HIF1alpha, may thus bind HIF‐1beta and activate transcription of target genes. (C) Under severely hypoxic conditions, PHD/FIH‐1‐mediated hydroxylations cannot occur, and both HIFs are rapidly stabilized, and can interact with HIF‐1beta to activate downstream target genes.