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.

中文翻译：

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EGF 受体介导的 FUS 磷酸化促进其核转位和纤维化信号传导

胶原蛋白的过度积累会导致纤维化。整合素 α1β1 (Itgα1β1) 通过抑制磷酸化细胞质和核蛋白的 EGF 受体 (EGFR) 来减少胶原蛋白的产生，从而预防肾纤维化。为了阐明 Itgα1β1/EGFR 轴如何控制胶原合成，我们分析了 WT 和 Itgα1-null 肾细胞中核酪氨酸磷酸化蛋白的水平。我们发现，肉瘤中融合的 RNA-DNA 结合蛋白 (FUS) 的磷酸化在 Itgα1 缺失细胞中较高。FUS 含有 EGFR 靶向磷酸化位点，在 Itgα1 缺失细胞中，激活的 EGFR 会促进 FUS 磷酸化和核转位。核 FUS 与胶原 IV 启动子结合，开始基因转录，通过抑制 EGFR、下调 FUS 或表达 EGFR 靶向磷酸化位点中突变的 FUS 来减少基因转录。最后，抑制 FUS 核易位的细胞穿透肽会降低 FUS 核含量和 IV 型胶原转录。因此，EGFR 介导的 FUS 磷酸化调节 FUS 核转位和主要促纤维化胶原基因的转录。针对 FUS 核易位提供了一种新的抗纤维化疗法。