Chronic hypoxia regulates Cytoplasmic Polyadenylation Element Binding Protein 2 alternative splicing to promote HIF1a translation

Abstract

HIF1 (Hypoxia-inducible Factor 1) is a transcription factor that plays a crucial role in the hypoxia stress response. Its primary function is to return the cell to its homeostatic state following oxygen deprivation. However, chronic hypoxia exposure can cause irreversible physiological changes that can lead to pulmonary hypertension (PH) and the need for therapeutics to ameliorate these conditions is great and unmet. Previous studies in our lab have demonstrated that CPEB2 (cytoplasmic polyadenylation element binding protein 2) is a translational repressor of one of the HIF1 subunits: HIF1α. Our lab demonstrated that the alternatively spliced CPEB2A isoform of CPEB2 is a repressor of translation, while the CPEB2B isoform is a translational activator of HIF1α during hypoxia, suggesting a major regulatory role for CPEB2 AS in the pulmonary hypoxic response. Although it is well established that during hypoxia, HIF1α levels are dramatically upregulated due to a decrease in the degradation of this factor, we propose that during chronic hypoxia, the expression of HIF1α is maintained via a translational mechanism, likely alongside a decrease in proteolytic degradation. In this study we demonstrate that depletion of the CPEB2B splice isoform has an inhibitory effect on the translation of nascent HIF1α protein during chronic hypoxia, but not the acute phase. We further demonstrate that this pathway is dependent on the initiation factor eIF3H. Finally, we show data which indicate that CPEB2A and CPEB2B bind differentially to cytoplasmic polyadenylation element consensus sequences depending on surrounding sequence context. These findings are important, since they provide evidence for potential of CPEB2 to act as a therapeutic target for treating chronic hypoxia-related pulmonary diseases.

Emerging roles of alternative cleavage and polyadenylation (APA) in human disease

“…Zhou et al, 2020). Recently, the role of core polyadenylation factors like cytoplasmic polyadenylation element-binding protein 2 (CPEB2) is perceived as a therapeutic target during pulmonary fibrosis (Huang et al, 2018;Mayo et al, 2021). In addition to the above, proteins like transforming growth factor-β1 (TGF-β1) alters the 3′-UTR of mRNA to promote lung fibrosis (Ko et al, 2019).…”