4E-BP1-dependent translation in nociceptors controls mechanical hypersensitivity via TRIM32/type I interferon...

Area of Science:

• Neuroscience
• Molecular Biology
• Pain Research

Background:

• Mechanistic target of rapamycin complex 1 (mTORC1) activation is implicated in chronic pain development.
• The precise molecular mechanisms linking mTORC1 to pain hypersensitivity are not fully understood.
• Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) is a critical downstream effector of mTORC1, regulating translation initiation.

Purpose of the Study:

• To elucidate the specific mechanisms by which mTORC1 activation leads to pain hypersensitivity.
• To investigate the role of 4E-BP1 and its downstream targets in nociception.
• To identify potential therapeutic targets for inflammatory pain.

Main Methods:

• Nociceptor-specific deletion of 4E-BP1 in mice to mimic mTORC1 activation.
• Translating ribosome affinity purification (TRAP) in nociceptors to identify upregulated proteins.
• Assessment of mechanical hypersensitivity in genetically modified mice and after pharmacological interventions.
• Evaluation of TRIM32's role in inflammatory pain models.

Main Results:

• Deletion of 4E-BP1 in nociceptors induced mechanical hypersensitivity.
• Translational upregulation of tripartite motif-containing protein 32 (TRIM32) was identified in 4E-BP1-deficient nociceptors.
• Downregulation of TRIM32 or blockade of type I interferon signaling reversed hypersensitivity.
• Nociceptor-specific TRIM32 ablation alleviated inflammatory pain hypersensitivity.

Conclusions:

• mTORC1 activation in nociceptors promotes pain hypersensitivity through 4E-BP1-dependent translational upregulation of TRIM32.
• The TRIM32/interferon signaling pathway in nociceptors is crucial for mechanical hypersensitivity.
• TRIM32 represents a promising therapeutic target for managing inflammatory pain.