EGF receptor-mediated FUS phosphorylation promotes its nuclear translocation and fibrotic signaling

Area of Science:

• Cell Biology
• Molecular Biology
• Renal Physiology

Background:

• Excessive collagen accumulation causes fibrosis.
• Integrin α1β1 (Itgα1β1) inhibits kidney fibrosis by reducing collagen production via EGF receptor (EGFR) signaling.
• The precise mechanism by which the Itgα1β1/EGFR axis controls collagen synthesis remains unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying Itgα1β1/EGFR-mediated regulation of collagen synthesis.
• To investigate the role of nuclear protein phosphorylation in kidney fibrosis.
• To identify potential therapeutic targets for antifibrotic strategies.

Main Methods:

• Analysis of nuclear tyrosine phosphorylated proteins in wild-type (WT) and Itgα1-null kidney cells.
• Investigating the effect of EGFR inhibition on FUS phosphorylation and nuclear translocation.
• Assessing the impact of FUS modulation (mutation, inhibition of nuclear translocation) on collagen IV transcription.

Main Results:

• Phosphorylation of the RNA-DNA binding protein fused in sarcoma (FUS) is elevated in Itgα1-null kidney cells.
• Activated EGFR promotes FUS phosphorylation and subsequent nuclear translocation in Itgα1-null cells.
• Inhibition of EGFR, FUS downregulation, or mutated FUS reduced collagen IV transcription; a peptide inhibiting FUS nuclear translocation decreased collagen IV gene expression.

Conclusions:

• EGFR-mediated FUS phosphorylation is a critical regulator of FUS nuclear translocation and transcription of the profibrotic collagen IV gene.
• Targeting FUS nuclear translocation presents a novel therapeutic approach for treating kidney fibrosis.