Acetylation-dependent glutamate receptor GluR signalosome formation for STAT3 activation in both transcriptional and metabolism regulation

Xiang-Rong Li,Yan S Xu,Y Eugene Chin,Chao Huang,Yimei Hao,Nannan Chen,Jia Sun,Xiaju Cheng

doi:10.1038/s41420-020-00389-6

Abstract

Besides their original regulating roles in the brain, spinal cord, retina, and peripheral nervous system for mediating fast excitatory synaptic transmission, glutamate receptors consisting of metabotropic glutamate receptors (GluRs) and ionotropic glutamate receptors (iGluRs) have emerged to have a critical role in the biology of cancer initiation, progression, and metastasis. However, the precise mechanism underpinning the signal transduction mediated by ligand-bound GluRs is not clearly elucidated. Here, we show that iGluRs, GluR1 and GluR2, are acetylated by acetyltransferase CREB-binding protein upon glutamate stimulation of cells, and are targeted by lysyl oxidase-like 2 for deacetylation. Acetylated GluR1/2 recruit β-arrestin1/2 and signal transducer and activator of transcription 3 (STAT3) to form a protein complex. Both β-arrestin1/2 and STAT3 are subsequently acetylated and activated. Simultaneously, activated STAT3 acetylated at lysine 685 translocates to mitochondria to upregulate energy metabolism-related gene transcription. Our results reveal that acetylation-dependent formation of GluR1/2–β-arrestin1/2–STAT3 signalosome is critical for glutamate-induced cell proliferation.

Highlights

Glutamate receptors (GluRs), the major excitatory receptor in the brain, are characterized as ionotropic or metabotropic
Glutamate-induced acetylation of both GluR1 and GluR2 To explore the role of acetylation in ionotropic glutamate receptors (iGluRs), GluR1 and
Results show that both GluR1 and GluR2 were subjected to acetylation by CREB-binding protein (CBP) (Fig. 1c, d)

Summary

Introduction

Glutamate receptors (GluRs), the major excitatory receptor in the brain, are characterized as ionotropic or metabotropic. Ionotropic GluRs are tetrameric ligandgated cation channels that induce depolarization of the postsynaptic membrane, following the presynaptic release of glutamate. Their actions underlie the cellular models of learning and memory, modulate the excitability of neuronal networks, and are required for synaptic maturation. Ionotropic GluRs can be pharmacologically classified according to their sensitivity to AMPA, Kainate, and NMDA. Precise mechanism underlying the functional role of GluRs in cancer initiation and progression is unclear

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Conclusion