biostudies-literatureChiusa MBLRD VANIDDK NIH HHSNational Institutes of HealthDepartment of Veterans Affairse202001120https://www.ebi.ac.uk/biostudies/studies/S-EPMC7480104biostudies-literatureUnknown219(9)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.The Journal of cell biologyEGF receptor-mediated FUS phosphorylation promotes its nuclear translocation and fibrotic signaling.PMC74801041I01BX002196R01-DK56942R0-1-DK051265R01 DK051265R01-DK099467R01 DK056942I01 BX002750R01 DK095785I01 BX002025101BX002750101BX000320I01 BX002196P30 DK114809I01 BX000320R01-DK119212R01 DK099467IK6 BX005240R01-DK069921R01 DK062794R01 DK1192121I01BX002025R01 DK069921P30-DK114809Chiusa MHu WPozzi AWilson MHZienkiewicz JFogo ABHawiger JBenigni AHarris RCMili SZhang MZBentz JAZent RRemuzzi GVanacore RMLuo WChen XfalseEGF receptor-mediated FUS phosphorylation promotes its nuclear translocation and fibrotic signaling.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.2020-01-01T00:00:00Z2020 Sep2026-05-03T08:39:19.904Z2021-03-09T08:18:04ZS-EPMC74801043267888110.1083/jcb.202001120