A variant of death-receptor 3 associated with rheumatoid arthritis interferes with apoptosis-induction of T cell

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Abstract

Rheumatoid arthritis (RA) is a chronic polyarthritis of unknown etiology. To unravel the molecular mechanisms in RA, we performed targeted DNA sequencing analysis of patients with RA. This analysis identified a variant of the death receptor 3 (DR3) gene, a member of the family of apoptosis-inducing Fas genes, which contains four single-nucleotide polymorphisms (SNPs) and a 14-nucleotide deletion within exon 5 and intron 5. We found that the deletion causes the binding of splicing regulatory proteins to DR3 pre-mRNA intron 5, resulting in a portion of intron 5 becoming part of the coding sequence, thereby generating a premature stop codon. We also found that this truncated DR3 protein product lacks the death domain and forms a heterotrimer complex with wildtype DR3 that dominant-negatively inhibits ligand-induced apoptosis in lymphocytes. Myelocytes from transgenic mice expressing the human DR3 variant produced soluble truncated DR3, forming a complex with TNF-like ligand 1A (TL1A), which inhibited apoptosis induction. In summary, our results reveal that a DR3 splice variant that interferes with ligand-induced T cell responses and apoptosis may contribute to RA pathogenesis.

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Hashiramoto, A., Konishi, Y., Murayama, K., Kawasaki, H., Yoshida, K., Tsumiyama, K., … Shiozawa, S. (2018). A variant of death-receptor 3 associated with rheumatoid arthritis interferes with apoptosis-induction of T cell. Journal of Biological Chemistry, 293(6), 1933–1943. https://doi.org/10.1074/jbc.M117.798884

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