Characterization of USP11 as a novel regulator of Hypoxia inducible factor a

Abstract

Adaptation to hypoxia is a puzzling and tightly regulated challenge. This adaptability involves a severe gene expression rewiring, which is mainly triggered by the Hypoxia Inducible transcription Factor (HIF). Canonically, the regulation of the hypoxia signalling pathway mostly relies on HIF-¿ subunit, which has been described to be exquisitely regulated through the Ubiquitin Proteasome System (UPS).Because of the Ub conjugation¿ crucial role in the hypoxia pathway and in light with DUBs being druggable enzymes, we carried out an unbiased loss-of function screen to identify new DUBs modulating HIF signalling. Using this strategy, we identified 12 novel hypoxia-related DUBs. In this project, we have validated the hit candidates and further focused on USP11 characterization. We have shown that USP11 is required to sustain hypoxia-driven signalling. Indeed, USP11 binds the mRNA-binding protein, hnRNPD, forming a ribonucleoprotein complex that controls HIF1A mRNA turnover by hnRNPD-mediated interaction with HIF1A 3¿UTR. Consistent with the decrease in HIF1A mRNA upon hypoxia, we have shown that hypoxia inhibits USP11 activity and promotes hnRNPD/p37 nuclear accumulation. Therefore, USP11-mediated HIF1A post-transcriptional regulation reveals a new mechanism to fine tune HIF signalling and hypoxia adaptation, and might represent a new opportunity to understand the pathology of Lyme disease.