Excessive accumulation of collagen leads to fibrosis. Integrin α1β1 (Itgα1β1) prevents kidney fibrosis by reducing collagen production through inhibition of the EGF receptor (EGFR) that phosphorylates cytoplasmic and nuclear proteins. To elucidate how the Itgα1β1/EGFR axis controls collagen synthesis, we analyzed the levels of nuclear tyrosine phosphorylated proteins in WT and Itgα1-null kidney cells. We show that the phosphorylation of the RNA-DNA binding protein fused in sarcoma (FUS) is higher in Itgα1-null cells. FUS contains EGFR-targeted phosphorylation sites and, in Itgα1-null cells, activated EGFR promotes FUS phosphorylation and nuclear translocation. Nuclear FUS binds to the collagen IV promoter, commencing gene transcription that is reduced by inhibiting EGFR, down-regulating FUS, or expressing FUS mutated in the EGFR-targeted phosphorylation sites. Finally, a cell-penetrating peptide that inhibits FUS nuclear translocation reduces FUS nuclear content and collagen IV transcription. Thus, EGFR-mediated FUS phosphorylation regulates FUS nuclear translocation and transcription of a major profibrotic collagen gene. Targeting FUS nuclear translocation offers a new antifibrotic therapy.
EGF receptor–mediated FUS phosphorylation promotes its nuclear translocation and fibrotic signaling
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Manuel Chiusa, Wen Hu, Jozef Zienkiewicz, Xiwu Chen, Ming-Zhi Zhang, Raymond C. Harris, Roberto M. Vanacore, Jennifer A. Bentz, Giuseppe Remuzzi, Ariela Benigni, Agnes B. Fogo, Wentian Luo, Stavroula Mili, Matthew H. Wilson, Roy Zent, Jacek Hawiger, Ambra Pozzi; EGF receptor–mediated FUS phosphorylation promotes its nuclear translocation and fibrotic signaling. J Cell Biol 7 September 2020; 219 (9): e202001120. doi: https://doi.org/10.1083/jcb.202001120
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