Large-scale activity assignment of RNA-interacting proteins identifies a functional antagonist to fragile X mental retardation protein

RNA binding proteins (RBPs) impact cellular protein levels by regulating messenger RNA (mRNA) levels. Assignment of function to hundreds of emerging, uncharacterized RBPs is a critical bottleneck to a complete understanding of gene expression control. Here, large-scale tethering of nearly a thousand RBPs discovers 50 RBPs that affect reporter RNA turnover and translation. Enhanced UV crosslinking and immunoprecipitation (eCLIP) identify hundreds of endogenous mRNA targets affected by manipulating levels of more than a dozen candidate RBPs. Among these candidates, we characterize the ubiquitin-associated protein 2-like (UBAP2L) gene. Polysome profiling assays indicate that UBAP2L enhances translation of target mRNAs, likely due to ribosome interactions as supported by eCLIP data. UBAP2L can also be found in complex with fragile X mental retardation protein FMRP, and 52% of UBAP2L mRNA targets are also FMRP targets. UBAP2L depletion in a cortical neuronal model of Fragile X Syndrome (FXS) corrects molecular, cellular and electrophysiological defects relevant to autism spectrum disorder. Reduction of the Drosophila ortholog of UBAP2L in a FXS fly model rescues the neurodevelopmental defects due to loss of FMRP. Our efficient and scalable method identifies proteins involved in RNA metabolism and detailed studies of UBAP2L provides a new therapeutic strategy into human disease