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

Autor:	Chiusa M; Department of Medicine, Division of Nephrology and Hypertension, and., Lee YA; Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Zhang MZ; Department of Medicine, Division of Nephrology and Hypertension, and., Harris RC; Department of Medicine, Division of Nephrology and Hypertension, and.; Department of Veterans Affairs, Nashville, Tennessee, USA., Sherrill T; Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Lindner V; Center for Molecular Medicine, Maine Health Institute for Research, Scarborough, Maine, USA., Brooks CR; Department of Medicine, Division of Nephrology and Hypertension, and., Yu G; Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA., Fogo AB; Department of Medicine, Division of Nephrology and Hypertension, and.; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Flynn CR; Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Zienkiewicz J; Department of Veterans Affairs, Nashville, Tennessee, USA.; Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Hawiger J; Department of Veterans Affairs, Nashville, Tennessee, USA.; Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Zent R; Department of Medicine, Division of Nephrology and Hypertension, and.; Department of Veterans Affairs, Nashville, Tennessee, USA., Pozzi A; Department of Medicine, Division of Nephrology and Hypertension, and.; Department of Veterans Affairs, Nashville, Tennessee, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2024 Mar 15; Vol. 134 (6). Date of Electronic Publication: 2024 Mar 15.
DOI:	10.1172/JCI175158
Abstrakt:	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.
Databáze:	MEDLINE
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