TIGAR Suppresses ER Stress-Induced Neuronal Injury through Targeting ATF4 Signaling in Cerebral Ischemia/Reperfusion.

Abstract

Endoplasmic reticulum (ER) stress is crucial in cerebral ischemia/reperfusion injury by triggering cellular apoptosis and exacerbating neuronal damage. This study elucidates the dynamics of TP53-induced glycolysis and apoptosis regulator (TIGAR) translocation and its role in regulating neural fate during cerebral ischemia-induced ER stress, specifically in male mice. We found enhanced nuclear localization of TIGAR in neurons after transient middle cerebral artery occlusion/reperfusion (tMCAO/R) in male mice, as well as oxygen glucose deprivation/reperfusion (OGD/R) and treatment with ER stress inducer (tunicamycin and thapsigargin) in neuronal cells. Conditional neuronal knockdown of Tigar aggravated the injury following ischemia-reperfusion, whereas overexpression of Tigar attenuated cerebral ischemic injury and ameliorated intraneuronal ER stress. Additionally, TIGAR overexpression reduced the elevation of ATF4 target genes and attenuated ER stress-induced cell death. Notably, TIGAR colocalized and interacted with ATF4 in the nucleus, inhibiting its downstream proapoptotic gene transcription, consequently protecting against ischemic injury. In vitro and in vivo experiments revealed that ATF4 overexpression reversed the protective effects of TIGAR against cerebral ischemic injury. Intriguingly, our study identified the Q141/K145 residues of TIGAR, crucial for its nuclear translocation and interaction with ATF4, highlighting a novel aspect of TIGAR's function distinct from its known phosphatase activity or mitochondrial localization domains. These findings reveal a novel neuroprotective mechanism of TIGAR in regulating ER stress through ATF4-mediated signaling pathways. These insights may guide targeted therapeutic strategies to protect neuronal function and alleviate the deleterious effects of cerebral ischemic injury.