The integrated stress response regulates BMP signalling through effects on translation

Area of Science:

• Molecular Biology
• Developmental Biology
• Cell Signaling

Background:

• Environmental responsiveness is crucial for developmental pathways.
• The integrated stress response (ISR), triggered by eIF2α phosphorylation, influences survival and development.
• Bone morphogenetic proteins (BMPs) are key regulators of development across species.

Purpose of the Study:

• To investigate the interplay between the ISR and BMP signaling in Drosophila development.
• To elucidate the molecular mechanisms by which ISR components modulate BMP signaling.

Main Methods:

• Utilized Drosophila as a model organism.
• Manipulated GCN2 kinase activity and eIF2α phosphatase levels.
• Assessed BMP signaling through translational and transcriptional regulation.
• Examined the role of the transcription factor crc (dATF4) and its target d4-BP.

Main Results:

• GCN2 antagonizes BMP signaling via direct translational effects and indirect transcriptional regulation through crc (dATF4).
• Constitutively active GCN2 or impaired eIF2α dephosphorylation hinders developmental BMP signaling.
• ISR-mediated translation inhibition blocks downstream BMP signaling.
• Loss of d4-BP enhances BMP signaling and rescues tissue development.

Conclusions:

• Identified a novel mechanism where the ISR modulates BMP signaling during development.
• Demonstrated a direct link between stress response pathways and developmental signaling networks.