The antiviral protein viperin regulates chondrogenic differentiation via CXCL10 protein secretion

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 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 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.

ddhCTP produced by the radical‐SAM activity of RSAD2 (viperin) inhibits the NAD+‐dependent activity of enzymes to modulate metabolism

“…In addition to the widely studied broad‐spectrum antiviral function of RSAD2 [7–14], emerging evidence suggests the enzyme may play a role in a range of different cellular processes. RSAD2 plays a role in optimal Th2 response [15], regulates thermogenesis in adipose tissue [16], is required for Golgi trafficking of TNF‐α in activated microglia [17], and regulates chondrogenic differentiation via CXCL10 protein secretion [18]. The radical‐SAM activity of RSAD2 can abolish metabolism of amino acids and mitochondrial respiration [19].…”

Metatranscriptomics to characterize respiratory virome, microbiome, and host response directly from clinical samples

“…RSV-ARI (n=32) and HC (n=12) samples were used for gene expression analysis using DESeq2 17 , which revealed that 2,878 genes were upregulated and 1,746 genes were down-regulated in RSV-ARI subjects (Figure 5a and Supplementary Table S6). Most of the overexpressed genes are involved in immune response during RSV infection, speci cally interferon response genes, IFIT1, IFIT2, IFIT3, IFI6, and antiviral genes such as IFITM3 18 , IFITM1 19 and MX1 20 , as well as chemokines CCL4, CCL8 and CXCL10 21 . We also identi ed ACOD1 as being signi cantly upregulated in RSV-ARI samples.…”

Insights Into the Molecular Mechanism of Deer Antler Extract Serving as a Potential Chondroprotective Agent for Articular Cartilage

“…All of them are signi cantly expressed in the articular chondrocytes, and Ca2 is mainly localized in the proliferating chondrocytes [44]. Rsad2, also known as viperin, is highly expressed in the middle zone of articular cartilage [45]. Tal1 is a basic helix-loop-helix transcription factor in the articular chondrocytes, and serves as a crucial regulator during chondrocyte maturation [46].…”