Abstract

BACKGROUND: Cardiomyocyte growth is coupled with active protein synthesis, which is one of the basic biological processes in living cells. However, it is unclear whether the unfolded protein response transducers and effectors directly take part in the control of protein synthesis. The connection between critical functions of the unfolded protein response in cellular physiology and requirements of multiple processes for cell growth prompted us to investigate the role of the unfolded protein response in cell growth and underlying molecular mechanisms. METHODS: Cardiomyocyte-specific inositol-requiring enzyme 1? (IRE1?) knockout and overexpression mouse models were generated to explore its function in vivo. Neonatal rat ventricular myocytes were isolated and cultured to evaluate the role of IRE1? in cardiomyocyte growth in vitro. Mass spectrometry was conducted to identify novel interacting proteins of IRE1?. Ribosome sequencing and polysome profiling were performed to determine the molecular basis for the function of IRE1? in translational control. RESULTS: We show that IRE1? is required for cell growth in neonatal rat ventricular myocytes under prohypertrophy treatment and in HEK293 cells in response to serum stimulation. At the molecular level, IRE1? directly interacts with eIF4G and eIF3, 2 critical components of the translation initiation complex. We demonstrate that IRE1? facilitates the formation of the translation initiation complex around the endoplasmic reticulum and preferentially initiates the translation of transcripts with 5’ terminal oligopyrimidine motifs. We then reveal that IRE1? plays an important role in determining the selectivity and translation of these transcripts. We next show that IRE1? stimulates the translation of epidermal growth factor receptor through an unannotated terminal oligopyrimidine motif in its 5’ untranslated region. We further demonstrate a physiological role of IRE1?-governed protein translation by showing that IRE1? is essential for cardiomyocyte growth and cardiac functional maintenance under hemodynamic stress in vivo. CONCLUSIONS: These studies suggest a noncanonical, essential role of IRE1? in orchestrating protein synthesis, which may have important implications in cardiac hypertrophy in response to pressure overload and general cell growth under other physiological and pathological conditions. © 2024 American Heart Association, Inc.