Regulation of Protein Synthesis at the Translational Level: Novel Findings in Cardiovascular Biology

Figures

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  Figure 1. Main methods of translational study in the heart. (A) Summary of Ribo-Seq. Ribosome-protected RNA fragments are digested and sequenced to detect ribosomal footprints. (B) Summary of RiboTag. The cardiomyocyte-specific promoter drives the expression of Cre, inducing the expression of a cell-type-specific HA-tagged RPL22 ribosomal protein. Anti-HA antibodies are used to separate the labeled ribosomes, and RNA is isolated for deep sequencing. (C) Summary of SUnSET Assay. Cells are incubated with puromycin. Translating mRNA is tagged with puromycin, and anti-puromycin antibodies are used for the quantification of signals.

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  Figure 2. Global regulation of protein synthesis. (A) 43S-mRNA complex formation. Translational initiation is regulated by interactions between PABPC1 and initiation factors. (B) mTOR regulation. mTORC1 regulates both initiation complex formation and translational elongation. (C) tRNA delivery. TIP30 regulates elongation by delivering tRNA aminoacyl tRNAs to the translating ribosome. (D) Unfolded protein response. IRE1α regulates interactions between eIF4G and eIF3.

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  Figure 3. Novel mechanisms of regulation in cardiac pathology. (A) Microtubular distribution of translation. Spatial distribution of translating ribosomes in hypertrophying cardiomyocytes requires proper microtubule assembly and functioning motor proteins. (B) uORF-dsRNA interactions. uORF translation is enhanced by resident dsRNA on Gata4 mRNA, inhibiting mORF translation and reducing CM hypertrophy. (C) Aminoacyl-tRNA synthesis dysregulation. Eprs knockout leads to an inability to synthesize proline-tRNAs, reducing the translation of proline-rich ECM proteins, hence inhibiting fibrosis formation. (D) Ribosome heterogeneity. RPL3L ribosomes are necessary for avoiding ribosome stalling and collisions, with Rpl3l knockout resulting in decreased synthesis of cardiac contractility-proteins and subsequent DCM pathology. (E) Stress granule formation. The pathogenic variant of RBM20 increases the formation of stress granules, which sequester mRNA and translational machinery, resulting in decreased protein synthesis at Z-discs and contributing to DCM pathology. (F) Localized translation by RBPs. hnRNPC translocates to the Z-discs during post-MI recovery, where it enhances the local translation of…

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  Figure 4. Mitochondrial protein synthesis regulation. (A) Mitochondrial ribosome generation. Heterozygous Mrps5 knockout results in a modest decrease in mitochondrial protein synthesis, resulting in increased regeneration after a myocardial infarction. Homozygous knockout results in more dramatic inhibition of mitochondrial protein synthesis, causing decreased heart function. (B) Mitochondrial elongation factor recruitment. Ago2 knockout prevents TUFM recruitment to mitochondrial mRNA, reducing ETC Complex III protein translation, inhibiting mitochondrial function, and contributing to diabetic cardiomyopathy pathology. (C) Mitochondrial elongation factor anchoring. FAM210A is necessary for the anchoring of TUFM to the mitochondrial membrane, and its knockout results in decreased mitochondrial protein synthesis, activation of the ISR stress pathway, and inhibition of cap-dependent translation, manifesting in heart failure.

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  Figure 5. Overview of translational regulation in the heart.