Poster abstracts
Poster number 131 submitted by Joe Seimetz
Translational control of cardiac hypertrophy: Poly(A) binding protein C1 at the heart of it
Sandip Chorghade (University of Illinois Urbana-Champaign Department of Biochemistry), Joe Seimetz (University of Illinois Urbana-Champaign Department of Biochemistry), Russel S. Emmons, Michael De Lisio (University of Illinois Urbana-Champaign Department of Kinesiology and Community Health), Stefan M. Bresson, Nicholas K. Conrad (University of Texas Southwestern Medical Center), Auinash Kalsotra (University of Illinois Urbana-Champaign Department of Biochemistry)
Abstract:
Poly(A) binding proteins (PABPs) are multifunctional scaffolds that bind to the poly(A) tail to form ribonucleoproteins determining the post-transcriptional fate of mRNAs including their export, stability, and translation. Based on these central roles, PABPs are considered essential for cell survival and function. Here we report that cytosolic PABPC1 protein expression is post-transcriptionally silenced in the adult human and murine hearts. Strikingly, the silencing is cardiomyocyte-specific, evolutionarily conserved, and reversed with endurance exercise and in heart disease. We demonstrate that PABPC1 silencing is driven by its poly(A) tail length shortening during postnatal heart development, which results in reduced polysome association and translation of Pabpc1 transcripts. Furthermore, we demonstrate that PABPC1-depleted neonatal cardiac myocytes are viable; but refractory to stimulus-induced hypertrophic growth due to their inability to initiate new protein synthesis. Remarkably, forced expression of PABPC1 in the adult myocardium of transgenic mice stimulates physiologic hypertrophy by enhancing global translation, which is dependent on eukaryotic initiation factor (eIF)4G-PABPC1 interactions and mRNA circularization. Supplementing PABPC1-deficient cardiomyocytes with wildtype PABPC1 rescues, whereas a mutant form of PABPC1–engineered by Structure-guided mutations to disrupt eIF4G-PABPC1 interactions–fails to rescue the hypertrophic growth and translation defects in these cells. Taken together, our results uncover a cell-type and developmental stage-specific function for PABPC1 and reveal its upregulation as a central mechanism in activating cardiac hypertrophy in response to physiologic and pathologic stimuli.
Keywords: Translation, Poly(A) Tail, post-transcriptional regulation