Journal Article

Cytoplasmic retention of the DNA/RNA-binding protein FUS ameliorates organ fibrosis in mice

Lee, Youngmin A., Flynn, Charles R., Chiusa, Manuel, Zhang, Ming-Zhi, Harris, Raymond C., Zienkiewicz, Jozef, Lindner, Volkhard, Hawiger, Jacek, Zent, Roy, Fogo, Agnes B., Yu, Gang, Sherrill, Taylor, Brooks, Craig R., Pozzi, Ambra

2024

Overview

Uncontrolled accumulation of extracellular matrix leads to tissue fibrosis and loss of organ function. We previously demonstrated in vitro that the DNA/RNA-binding protein fused in sarcoma (FUS) promotes fibrotic responses by translocating to the nucleus, where it initiates collagen gene transcription. However, it is still not known whether FUS is profibrotic in vivo and whether preventing its nuclear translocation might inhibit development of fibrosis following injury. We now demonstrate that levels of nuclear FUS are significantly increased in mouse models of kidney and liver fibrosis. To evaluate the direct role of FUS nuclear translocation in fibrosis, we used mice that carry a mutation in the FUS nuclear localization sequence (FUSR521G) and the cell-penetrating peptide CP-FUS-NLS that we previously showed inhibits FUS nuclear translocation in vitro. We provide evidence that FUSR521G mice or CP-FUS-NLS-treated mice showed reduced nuclear FUS and fibrosis following injury. Finally, differential gene expression analysis and immunohistochemistry of tissues from individuals with focal segmental glomerulosclerosis or nonalcoholic steatohepatitis revealed significant upregulation of FUS and/or collagen genes and FUS protein nuclear localization in diseased organs. These results demonstrate that injury-induced nuclear translocation of FUS contributes to fibrosis and highlight CP-FUS-NLS as a promising therapeutic option for organ fibrosis.

• Publisher: American Society for Clinical Investigation
• Subject: Amyotrophic Lateral Sclerosis - genetics / Animal models / Animals / Collagen / Collagen - metabolism / Cytoplasm / Development and progression / DNA / DNA binding proteins / DNA-Binding Proteins - genetics / Epidermal growth factor / Extracellular matrix / Fatty liver / Fibrosis / FUS gene / FUS protein / Gene expression / Genetic aspects / Health aspects / Hepatology / Immunohistochemistry / Kidneys / Kinases / Liver / Localization / Mice / Mutation / Nephrology / Nuclear transport / Peptides / Phosphorylation / Physiological aspects / Proteins / RNA / RNA-binding protein / RNA-Binding Protein FUS - genetics / RNA-Binding Protein FUS - metabolism / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Sarcoma / Translocation (Genetics)