Smaug/SAMD4A Restores Translational Activity of CUGBP1 and Suppresses CUG-Induced Myopathy

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. © 2013 de haro et al.