The antiviral protein viperin regulates chondrogenic differentiation via CXCL10 protein secretion.

Steinbusch, Mandy MF, Caron, Marjolein MJ, Surtel, Don AM, van den Akker, Guus GH, van Dijk, Paul J, Friedrich, Franziska, Zabel, Bernhard, van Rhijn, Lodewijk W, Peffers, Mandy J ORCID: 0000-0001-6979-0440 and Welting, Tim JM (2019) The antiviral protein viperin regulates chondrogenic differentiation via CXCL10 protein secretion. The Journal of Biological Chemistry, 294 (13). pp. 5121-5136.

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Abstract

Viperin (also known as radical SAM domain-containing 2, RSAD2) is an interferon-inducible and evolutionary conserved protein that participates in the cell's innate immune response against a number of viruses. Viperin mRNA is a substrate for endoribonucleolytic cleavage by RNase mitochondrial RNA processing (MRP) and mutations in the RMRP small nucleolar RNA (snoRNA) subunit of the RNase MRP complex cause cartilage-hair hypoplasia (CHH), a human developmental condition characterized by metaphyseal chondrodysplasia and severe dwarfism. It is unknown how CHH-pathogenic mutations in RMRP snoRNA interfere with skeletal development and aberrant processing of RNase MRP substrate RNAs is thought to be involved. We hypothesized that viperin plays a role in chondrogenic differentiation. Using immunohistochemistry, RT-qPCR, immunoblotting, ELISA, siRNA-mediated gene silencing, plasmid-mediated gene overexpression, label-free mass-spectrometry proteomics and promoter reporter bioluminescence assays, we discovered here that viperin is expressed in differentiating chondrocytic cells and regulates their protein secretion and the outcome of chondrogenic differentiation by influencing transforming growth factor β (TGF-β)/SMAD family 2/3 (SMAD2/3) activity via C-X-C motif chemokine ligand 10 (CXCL10). Of note, we observed disturbances in this viperin-CXCL10-TGF-β/SMAD2/3 axis in CHH chondrocytic cells. Our results indicate that the anti-viral protein viperin controls chondrogenic differentiation by influencing secretion of soluble proteins and identify a molecular route that may explain impaired chondrogenic differentiation of cells from individuals with CHH.

Item Type:	Article
Uncontrolled Keywords:	cartilage biology, chondrogenesis, small nucleolar RNA (snoRNA), transforming growth factor beta (TGF-B), chemokine, secretion, C-X-C motif chemokine ligand 10, cartilage-hair hypoplasia, chondrogenic differentiation, RMRP snoRNA, viperin
Depositing User:	Symplectic Admin
Date Deposited:	15 Feb 2019 09:24
Last Modified:	19 Jan 2023 01:03
DOI:	10.1074/jbc.ra119.007356
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3032852