Noncanonical feedback loop between "RIP3-MLKL" and "4EBP1-eIF4E" promotes neuronal necroptosis

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Death Research

Background:

• Stroke is a major cause of death and disability.
• Necroptosis, a regulated form of necrosis, plays a role in stroke pathogenesis.
• The precise molecular mechanisms of necroptosis in stroke are not fully understood.

Purpose of the Study:

• To investigate the role of the 4EBP1-eIF4E pathway in necroptosis during stroke.
• To elucidate the relationship between the 4EBP1-eIF4E pathway and the RIP3-MLKL necroptosis pathway.

Main Methods:

• Utilized necroptotic HT-22 cells and a mouse middle cerebral artery occlusion (MCAO) model.
• Examined the activation status of the 4EBP1-eIF4E pathway in these models.
• Investigated the functional impact of modulating 4EBP1 and eIF4E on necroptosis.
• Analyzed the feedback interaction between the 4EBP1-eIF4E and RIP3-MLKL pathways.
• Assessed the therapeutic potential of inhibiting eIF4E, RIP3, and MLKL in the MCAO model.

Main Results:

• The 4EBP1-eIF4E pathway was activated in both in vitro and in vivo stroke models.
• Overexpression of 4EBP1, knockdown of eIF4E, or inhibition of eIF4E suppressed necroptosis.
• A positive feedback loop was identified where RIP3-MLKL signaling degrades 4EBP1 and activates eIF4E, which in turn enhances RIP3-MLKL activity.
• eIF4E activation may promote cytokine production, contributing to necroptosis.
• Inhibition of eIF4E, RIP3, and MLKL reduced infarct volume and improved neurological function in MCAO mice.

Conclusions:

• The 4EBP1-eIF4E pathway is a key regulator of necroptosis in stroke.
• A positive feedback circuit between the 4EBP1-eIF4E and RIP3-MLKL pathways drives necroptosis.
• Targeting the eIF4E, RIP3, and MLKL pathways shows therapeutic promise for stroke treatment.