Smaug/SAMD4A Restores Translational Activity of CUGBP1 and Suppresses CUG-Induced Myopathy |
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Authors: | Maria de Haro Ismael Al-Ramahi Karlie R Jones Jerrah K Holth Lubov T Timchenko Juan Botas |
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Institution: | 1.Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America;2.Jan and Dan Duncan Neurological Research Institute, Texas Children''s Hospital, Houston, Texas, United States of America;3.Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States of America;The Jackson Laboratory, United States of America |
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Abstract: | We report the identification and characterization of a previously unknown suppressor of myopathy caused by expansion of CUG repeats, the mutation that triggers Myotonic Dystrophy Type 1 (DM1). We screened a collection of genes encoding RNA–binding proteins as candidates to modify DM1 pathogenesis using a well established Drosophila model of the disease. The screen revealed smaug as a powerful modulator of CUG-induced toxicity. Increasing smaug levels prevents muscle wasting and restores muscle function, while reducing its function exacerbates CUG-induced phenotypes. Using human myoblasts, we show physical interactions between human Smaug (SMAUG1/SMAD4A) and CUGBP1. Increased levels of SMAUG1 correct the abnormally high nuclear accumulation of CUGBP1 in myoblasts from DM1 patients. In addition, augmenting SMAUG1 levels leads to a reduction of inactive CUGBP1-eIF2α translational complexes and to a correction of translation of MRG15, a downstream target of CUGBP1. Therefore, Smaug suppresses CUG-mediated muscle wasting at least in part via restoration of translational activity of CUGBP1. |
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