C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis

Abstract

The variant rs26232, in the first intron of the chromosome 5 open reading frame 30 (C5orf30) locus, has recently been associated with both risk of developing rheumatoid arthritis (RA) and severity of tissue damage. The biological activities of human C5orf30 are unknown, and neither the gene nor protein show significant homology to any other characterized human sequences. The C5orf30 gene is present only in vertebrate genomes with a high degree of conservation, implying a central function in these organisms. Here, we report that C5orf30 is highly expressed in the synovium of RA patients compared with control synovial tissue, and that it is predominately expressed by synovial fibroblast (RASF) and macrophages in the lining and sublining layer of the tissue. These cells play a central role in the initiation and perpetuation of RA and are implicated in cartilage destruction. RASFs lacking C5orf30 exhibit increased cell migration and invasion in vitro, and gene profiling following C5orf30 inhibition confirmed up-regulation of genes involved in cell migration, adhesion, angiogenesis, and immune and inflammatory pathways. Importantly, loss of C5orf30 contributes to the pathology of inflammatory arthritis in vivo, because inhibition of C5orf30 in the collagen-induced arthritis model markedly accentuated joint inflammation and tissue damage. Our study reveal C5orf30 to be a previously unidentified negative regulator of tissue damage in RA, and this protein may act by modulating the autoaggressive phenotype that is characteristic of RASFs.

Characterization of candidate genes in inflammatory bowel disease–associated risk loci

“…We identified 34 gene pairs (36 unique genes) with significant changes in correlation from the healthy state to disease uninflamed and inflamed states (Supplemental Table 6). Recent studies offer insights into potential roles in IBD-relevant pathways for the proteins encoded by these genes, such as C1ORF106 in autophagy- dependent intracellular pathogen defense (37) and C5ORF30 in negative regulation of immune and inflammatory pathways (38), but the activities of many of the genes remain to be studied in the context of IBD or other immune-mediated diseases.…”

Detection and Comparative Analysis of Methylomic Biomarkers of Rheumatoid Arthritis

“…Furthermore, C5orf30 (a methylation biomarker cg17605604) was reported as a damaging regulator of tissue in RA, which is highly expressed in RA synovial fibroblast (RASF) involving joint destruction (Muthana et al, 2015). The clinical data analysis also demonstrated that the variant rs26232 in C5orf30 locus was testified to be associated with RA susceptibility and radiologic damage severity.…”

The nuclear transport receptor TNPO1 binds macrophage immunometabolism regulator MACIR via a PY-NLS motif

“…Expression of MACIR has been shown to have a significant impact on the immunometabolism of macrophages and fibroblasts in autoimmune conditions. It is highly expressed in the synovium of rheumatoid arthritis patients compared with control synovial tissue where it is predominately expressed by synovial fibroblasts and macrophage and loss of expression contributes to the pathology of inflammatory arthritis in vivo, with inhibition of MACIR in the collagen-induced arthritis model leading to accentuated joint inflammation and tissue damage (1). MACIR expression has been shown to regulate macrophage phenotype.…”

“…MACIR, previously named C5orf30, is a negative regulator of tissue damage and 26 inflammation in rheumatoid arthritis (RA). It is highly expressed in the synovium of 27 rheumatoid arthritis patients where it is predominately expressed by fibroblasts and 28 macrophages (1). Reduced MACIR expression is an early event in the pathogenesis of RA 29…”

“…(2). Loss of expression contributes to the pathology of inflammatory arthritis in vivo, with 32 inhibition of MACIR in the collagen-induced arthritis model leading to accentuated joint 33 inflammation and tissue damage, and an increased inflammatory phenotype in a zebrafish 34 model of wound healing (1,2). MACIR regulates macrophage cell phenotype, with increased 35 MACIR expression found in M2-like anti-inflammatory macrophages.…”