Poster abstracts
Poster number 43 submitted by Alexander Chen
Deciphering Function and Mechanism of eIF4G2 in mRNA Translation Regulation in Cardiomyocytes: Insights into Cardiac Health and Disease
Alexander chen (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry), Liuqing Yang (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry), Eng-Soon Khor (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry), Debojyoti (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry), Peng Yao (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry)
Abstract:
Eukaryotic translation initiation factor 4 gamma 2 (eIF4G2), a homolog of the central cap-dependent translation factor eIF4G1, functions in cap-independent or eIF4E-independent cap-dependent translation initiation, particularly under stress, suggesting its critical role in translation control. Our previous study indicates that eIF4G2 is upregulated in diseased human and mouse hearts. In cardiac fibroblasts under stress, eIF4G2 promotes the translation of profibrotic mRNAs, thereby driving cardiac fibroblasts-to-myofibroblast transition. Given eIF4G2’s influence on translation efficiency and its role in ECM-related pathways in fibroblasts, we hypothesize that it also plays a significant, yet unexplored role in cardiomyocytes (CMs) in translational control. To investigate this hypothesis, we employed cultured AC16 human CMs subjected to siRNA-mediated Eif4g2 knockdown. In CMs, activation of the integrated stress response (ISR) was observed, characterized by increased phosphorylation of eIF2α and upregulation of ISR genes. These molecular changes suggest that loss of eIF4G2 in CMs activates stress pathways, which may compensate for the disruption of translation. This observation is consistent with our preliminary data from a tamoxifen-inducible, CM-specific Eif4g2 conditional knockout (cKO) mouse model, where ISR activation accompanies early remodeling prior to overt dysfunction, as indicated by RNA-seq and mass spectrometry dual-omics analysis. These results provide the rationale for integrating cell and animal models in parallel. Ongoing research aims to delineate the specific mRNA subsets that rely on eIF4G2 for translation. We will combine multi-omics analyses in mouse hearts with CLIP-seq and 5'-UTR motif analysis in cultured CMs to define how eIF4G2 regulates selective translation programs. Together, this in vivo and in vitro combined approach will clarify the mechanistic role of eIF4G2 in maintaining translational homeostasis in CMs, which thereby preserves cardiac function.
Keywords: eIF4G2, Cardiomyocyte, Translational control