PQBP1 Modulates Protein Synthesis Through The Regulation Of EEF2 Phosphorylation

SCHOOL NAME: Southeast University PQBP1 gene encodes a widely expressed multifunctional protein,and its mutations in human are associated with Renpenning syndrome,a type of X-linked intellectual disability(XLID)and 95% of the patients have varying degrees of mental retardation.Patients with Renpenning syndrome have similar clinical symptoms including microcephaly,long face,short stature,lean body and other developmental defects.Pqbp1 is highly expressed in the nervous system and is strictly spatiotemporal regulated during development,suggesting that it plays an important role in neurodevelopment and cognitive function.Due to the characteristics of PQBP1 structure and location,people mainly focus on its nucleus functions of transcription and splicing.Its cytosol functions remain to be elucidated.Although previous studies have shown that d PQBP1 binds to ribosomal proteins to regulate the expression of specific genes.However,the molecular mechanism of PQBP1 regulating protein synthesis is not clear.In this study,we found that PQBP1 bind to translation elongation factor 2(eEF2)by immunoprecipitation and mass spectrometry.Using PQBP1-knockdown cell lines and Pqbp1-conditional-knockout mice as models,with the assay of biochemistry,cell biology and molecular biology,we revealed that PQBP1 specifically binds with nonphosphorylated eEF2 through its WW domain and suppresses eEF2 K mediated eEF2 phosphorylation at Thr-56 site,promotes translation elongation and protein synthesis.Subsequent electrophysiological and behavioral tests in pqbp1 conditional knockout mice revealed that the absence of PQBP1 in the hippocampus could damage the m Glu R-LTD process and affect its mediated learning and cognitive behavior.In addition,synthesized membrane-permeable PQBP1 WW domain peptide in vitro interferes with eEF2 K mediated phosphorylation of eEF2 in CA1 region of mice,which can regulate m Glu R-LTD and m Glu R-LTD related learning and cognitive behaviors.Cells synthesize proteins in a spatially and temporally restricted manner to meet functional demands.Translational elongation allows additional amino acids to be added to the growing peptide,which controls the efficiency and accuracy of protein synthesis.This study revealed PQBP1 as a novel regulator in translational elongation and m Glu RLTD,and this newly revealed regulator in eEF2K/eEF2 pathway also provides an excellent therapeutic target for various disease conditions,such as neural diseases,virus infection,and cancer.