PQBP1 promotes translational elongation and regulates hippocampal mGluR-LTD by suppressing eEF2 phosphorylation

Yuqian Shen; Zi Chao Zhang; Shanshan Cheng; An Liu; Jian Zuo; Shuting Xia; Xian Liu; Wenhua Liu; Zhengping Jia; Wei Xie; Junhai Han

doi:10.1016/j.molcel.2021.01.032

PQBP1 promotes translational elongation and regulates hippocampal mGluR-LTD by suppressing eEF2 phosphorylation

Mol Cell. 2021 Apr 1;81(7):1425-1438.e10. doi: 10.1016/j.molcel.2021.01.032. Epub 2021 Mar 3.

Authors

Yuqian Shen¹, Zi Chao Zhang², Shanshan Cheng¹, An Liu¹, Jian Zuo¹, Shuting Xia³, Xian Liu¹, Wenhua Liu¹, Zhengping Jia⁴, Wei Xie⁵, Junhai Han⁶

Affiliations

¹ School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China.
² School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China. Electronic address: zhangzc@seu.edu.cn.
³ Institute of Neuroscience, Soochow University, Suzhou 215000, China.
⁴ Neurosciences and Mental Health Program, Hospital for Sick Children, University of Toronto, Toronto, ON M5S 1A1, Canada.
⁵ School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
⁶ School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China; Department of Neurology, Affiliated ZhongDa Hospital, Institute of Neuropsychiatry, Southeast University, Nanjing, Jiangsu 210009, China. Electronic address: junhaihan@seu.edu.cn.

PMID: 33662272
DOI: 10.1016/j.molcel.2021.01.032

Abstract

Eukaryotic elongation factor 2 (eEF2) mediates translocation of peptidyl-tRNA from the ribosomal A site to the P site to promote translational elongation. Its phosphorylation on Thr56 by its single known kinase eEF2K inactivates it and inhibits translational elongation. Extensive studies have revealed that different signal cascades modulate eEF2K activity, but whether additional factors regulate phosphorylation of eEF2 remains unclear. Here, we find that the X chromosome-linked intellectual disability protein polyglutamine-binding protein 1 (PQBP1) specifically binds to non-phosphorylated eEF2 and suppresses eEF2K-mediated phosphorylation at Thr56. Loss of PQBP1 significantly reduces general protein synthesis by suppressing translational elongation. Moreover, we show that PQBP1 regulates hippocampal metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) and mGluR-LTD-associated behaviors by suppressing eEF2K-mediated phosphorylation. Our results identify PQBP1 as a novel regulator in translational elongation and mGluR-LTD, and this newly revealed regulator in the eEF2K/eEF2 pathway is also an excellent therapeutic target for various disease conditions, such as neural diseases, virus infection, and cancer.

Keywords: PQBP1; Renpenning syndrome; eEF2; mGluR-LTD; novel object recognition; phosphorylation; protein synthesis; spatial recognition; translational elongation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
HEK293 Cells
HeLa Cells
Hippocampus / metabolism*
Humans
Long-Term Synaptic Depression*
Mice
Mice, Knockout
Peptide Chain Elongation, Translational*
Peptide Elongation Factor 2 / genetics
Peptide Elongation Factor 2 / metabolism*
Phosphorylation
Receptors, Metabotropic Glutamate / biosynthesis*
Receptors, Metabotropic Glutamate / genetics

Substances

DNA-Binding Proteins
PQBP1 protein, human
Peptide Elongation Factor 2
Pqbp1 protein, mouse
Receptors, Metabotropic Glutamate