GCN2 in proteostasis: structural logic, signalling networks and disease.

Area of Science:

• Molecular Biology
• Cellular Biology
• Biochemistry

Background:

• Proteostasis, the balance of protein synthesis, folding, and degradation, is crucial for cellular health.
• Disruptions lead to misfolded protein accumulation and stress responses like the integrated stress response (ISR).
• GCN2 kinase is a key sensor of amino acid and ribosomal stress within the ISR.

Purpose of the Study:

• To review the role of GCN2 in linking nutrient sensing to translational control and metabolic adaptation.
• To explore GCN2's function in maintaining proteostasis.
• To discuss GCN2's therapeutic potential in diseases linked to protein misfolding and stress imbalance.

Main Methods:

• Literature review of GCN2's role in cellular stress responses.
• Analysis of GCN2's interaction with other regulatory networks (e.g., mTORC1).
• Examination of GCN2's involvement in pathologies such as neurodegeneration, cancer, and pulmonary vascular disease.

Main Results:

• GCN2 activation phosphorylates eIF2α, reducing global translation and boosting ATF4/CHOP synthesis.
• ATF4 drives transcriptional programs for amino acid metabolism, redox balance, autophagy, and proteasomal degradation.
• GCN2 modulates mTORC1, promotes autophagy, facilitates stress granule formation, and integrates various stress signals.

Conclusions:

• GCN2 is central to restoring proteostasis by coordinating translational control and metabolic adaptation.
• Dysregulated GCN2 activity contributes to diverse pathologies.
• Targeting GCN2 offers potential therapeutic strategies for diseases characterized by protein misfolding and stress pathway imbalance.