Poly(A) tail length regulates PABPC1 expression to tune translation in the heart

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The rate of protein synthesis in the adult heart is one of the lowest in mammalian tissues, but it increases substantially in response to stress and hypertrophic stimuli through largely obscure mechanisms. Here, we demonstrate that regulated expression of cytosolic poly(A)-binding protein 1 (PABPC1) modulates protein synthetic capacity of the mammalian heart. We uncover a poly(A) tail-based regulatory mechanism that dynamically controls PABPC1 protein synthesis in cardiomyocytes and thereby titrates cellular translation in response to developmental and hypertrophic cues. Our findings identify PABPC1 as a direct regulator of cardiac hypertrophy and define a new paradigm of gene regulation in the heart, where controlled changes in poly(A) tail length influence mRNA translation.Hundreds of thousands of different proteins are needed to build and maintain the cells in the human body. All proteins are produced when copies of genetic information in the form of molecules of messenger RNA (mRNAs) are translated by the ribosome. The rate at which proteins are made varies widely between different tissues and at different times. In particular, the adult heart has one of the lowest rates of protein production, though this rate can increase markedly during exercise and heart disease. The mechanisms that drive this kind of dynamic change in protein production remain unclear. A better understanding of this process would tell scientists more about how and why cells regulate the translation of mRNAs in general, and might uncover new ways for treating heart disease.Molecules of mRNA are composed of smaller building blocks called nucleotides. All mature mRNAs in humans have a long stretch at one end that contains the nucleotide adenosine – commonly referred to as A for short – repeated 200 to 300 times. This sequence is called the poly(A) tail, and specific proteins can bind to this tail and determine the final fate of the mRNA, such as how efficiently it is translated. One such poly(A) binding protein, called PABPC1, is known to promote mRNA translation.Now, Chorghade, Seimetz et al. examine how PABPC1 regulates protein production in mice and human cells. The experiments reveal that, before birth, ample amounts of PABPC1 are found in the heart, but that this protein is undetectable in the hearts of adults. Further experiments showed that the levels of the mRNA for PABPC1 in the heart are the same before birth and in adulthood. So why is the mRNA for PABPC1 translated inefficiently in adult hearts? In general, mRNAs with long tails tend to be translated more efficiently compared to those with short tails, and it turns out that the mRNA for PABPC1 has a substantially shorter poly(A) tail in the adult heart. This tail shortening limits the translation of this specific mRNA, which leads to reduced protein production.Chorghade, Seimetz et al. also showed that the length of the poly(A) tail on the mRNA and the levels of the PABPC1 protein are restored in adult hearts during a condition known as hypertrophy. This state of hypertrophy can be triggered by exercise or heart disease and is marked by an increase in the size of individual heart cells and enhanced protein production. Finally, Chorghade, Seimetz et al. found that experimentally raising the levels of PABPC1 in adult hearts could, by itself, make the heart cells produce more protein and the heart grow more. Further studies will explore if other mRNAs in the heart also undergo similar changes and whether this is a general mechanism for controlling protein production.




Chorghade, S., Seimetz, J., Emmons, R., Yang, J., Bresson, S. M., de Lisio, M., … Kalsotra, A. (2017). Poly(A) tail length regulates PABPC1 expression to tune translation in the heart. ELife, 6. https://doi.org/10.7554/eLife.24139

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