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

ABSTRACT: Excessive accumulation of collagen leads to fibrosis. Integrin ?1?1 (Itg?1?1) prevents kidney fibrosis by reducing collagen production through inhibition of the EGF receptor (EGFR) that phosphorylates cytoplasmic and nuclear proteins. To elucidate how the Itg?1?1/EGFR axis controls collagen synthesis, we analyzed the levels of nuclear tyrosine phosphorylated proteins in WT and Itg?1-null kidney cells. We show that the phosphorylation of the RNA-DNA binding protein fused in sarcoma (FUS) is higher in Itg?1-null cells. FUS contains EGFR-targeted phosphorylation sites and, in Itg?1-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.

SUBMITTER: Chiusa M 

PROVIDER: S-EPMC7480104 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature