IRE1α Mediates the Hypertrophic Growth of Cardiomyocytes Through Facilitating the Formation of Initiation Complex to Promote the Translation of TOP-Motif Transcripts

  • Circulation. 2024 Sep 24;150(13):1010-1029. doi: 10.1161/CIRCULATIONAHA.123.067606.
Chao Li  1  2 ,  Shiqian Li  3  4 ,  Guangyu Zhang  1 ,  Qinfeng Li  1 ,  Weidan Song  1 ,  Xiaoding Wang  1 ,  Jane A Cook  1  2 ,  Miesje van der Stoel  3  4 ,  Bradley W Wright  5  6  7 ,  Francisco Altamirano  8 ,  Erica L Niewold  9 ,  Jungsoo Han  10 ,  Garrett Kimble  10 ,  Pengfei Zhang  9 ,  Xiang Luo  1 ,  Hery Urra  11 ,  Herman I May  1 ,  Anwarul Ferdous  1 ,  Xue-Nan Sun  2 ,  Yingfeng Deng  9 ,  Elina Ikonen  3  4 ,  Claudio Hetz  12 ,  Randal J Kaufman  13 ,  Kezhong Zhang  14 ,  Thomas G Gillette  1 ,  Philipp E Scherer  2 ,  Joseph A Hill  1  10 ,  Jin Chen  5  6  7 ,  Zhao V Wang  1  9
Affiliations
  • 1. Division of Cardiology, Department of Internal Medicine (C.L., G.Z., Q.L., W.S., X.W., J.A.C., X.L., H.I.M., A.F., T.G.G., J.A.H., Z.V.W.), University of Texas Southwestern Medical Center, Dallas.
  • 2. Touchstone Diabetes Center, Department of Internal Medicine (C.L., J.A.C., X.-N.S., P.E.S.), University of Texas Southwestern Medical Center, Dallas.
  • 3. Department of Anatomy and Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Finland (S.L., M.v.d.S., E.I.).
  • 4. Minerva Foundation Institute for Medical Research, Helsinki, Finland (S.L., M.v.d.S., E.I.).
  • 5. Laboratory of Functional Genomics and Translational Control, Cecil H. and Ida Green Center for Reproductive Biology Sciences (B.W.W., J.C.), University of Texas Southwestern Medical Center, Dallas.
  • 6. Department of Pharmacology (B.W.W., J.C.), University of Texas Southwestern Medical Center, Dallas.
  • 7. Harold C. Simmons Comprehensive Cancer Center (B.W.W., J.C.), University of Texas Southwestern Medical Center, Dallas.
  • 8. Department of Cardiovascular Sciences, Houston Methodist Research Institute, TX (F.A.).
  • 9. Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA (E.L.N., P.Z., Y.D., Z.V.W.).
  • 10. Department of Molecular Biology (J.H., G.K., J.A.H.), University of Texas Southwestern Medical Center, Dallas.
  • 11. Facultad de Odontología y Ciencias de la Rehabilitación, Universidad San Sebastián, Bellavista, Santiago, Chile (H.U.).
  • 12. Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile (C.H.).
  • 13. Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA (R.J.K.).
  • 14. Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI (K.Z.).
PMID: 38836349 DOI: 10.1161/CIRCULATIONAHA.123.067606
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 1α (IRE1α) 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 IRE1α in cardiomyocyte growth in vitro. Mass spectrometry was conducted to identify novel interacting proteins of IRE1α. Ribosome Sequencing and polysome profiling were performed to determine the molecular basis for the function of IRE1α in translational control.

Results: We show that IRE1α 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, IRE1α directly interacts with eIF4G and eIF3, 2 critical components of the translation initiation complex. We demonstrate that IRE1α 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 IRE1α plays an important role in determining the selectivity and translation of these transcripts. We next show that IRE1α 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 IRE1α-governed protein translation by showing that IRE1α is essential for cardiomyocyte growth and cardiac functional maintenance under hemodynamic stress in vivo.

Conclusions: These studies suggest a noncanonical, essential role of IRE1α 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.

Keywords
EGFR protein; eukaryonic initiation factor; heart failure; unfolded protein response.