The antiviral protein viperin regulates chondrogenic differentiation via CXCL10 protein secretion

Mandy M. F. Steinbusch, Marjolein M. J. Caron, Don A. M. Surtel, Guus G. H. van den Akker, Paul J. van Dijk, Franziska Friedrich, Bernhard Zabel, Lodewijk W. van Rhijn, Mandy J. Peffers, Tim J. M. Welting*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Web of Science)

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 RNase MRP 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 RNase MRP 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, real-time quantitative PCR, immunoblotting, ELISA, siRNA-mediated gene silencing, plasmid-mediated gene overexpression, label-free MS 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 beta (TGF-beta)/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-beta/SMAD2/3 axis in CHH chondrocytic cells. Our results indicate that the antiviral 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.

Original languageEnglish
Pages (from-to)5121-5136
Number of pages16
JournalJournal of Biological Chemistry
Volume294
Issue number13
DOIs
Publication statusPublished - 29 Mar 2019

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
  • INTERFERON-INDUCIBLE PROTEIN
  • MESENCHYMAL STEM-CELLS
  • RNASE MRP
  • GENE-EXPRESSION
  • MESSENGER-RNA
  • GROWTH-FACTOR
  • INHIBITION
  • GAMMA
  • ACTIVATION
  • MUTATIONS

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