A variant of death-receptor 3 associated with rheumatoid arthritis interferes with apoptosis-induction of T cell.
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.
['Hashiramoto|Akira|A|', 'Konishi|Yoshitake|Y|', 'Murayama|Koichi|K|', 'Kawasaki|Hiroki|H|', 'Yoshida|Kohsuke|K|', 'Tsumiyama|Ken|K|', 'Tanaka|Kimie|K|', 'Mizuhara|Masaru|M|', 'Shiotsuki|Toshio|T|', 'Kitamura|Hitomi|H|', 'Komai|Koichiro|K|', 'Kimura|Tomoatsu|T|', 'Yagita|Hideo|H|', 'Shiozawa|Kazuko|K|', 'Shiozawa|Shunichi|S|']
D000818:Animals D017209:Apoptosis D001172:Arthritis, Rheumatoid D005091:Exons D006801:Humans D007438:Introns D051379:Mice D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D020641:Polymorphism, Single Nucleotide D000072417:Protein Domains D053219:Receptors, Tumor Necrosis Factor, Member 25 D015398:Signal Transduction D013601:T-Lymphocytes D053380:Tumor Necrosis Factor Ligand Superfamily Member 15
arthritis death domain apoptosis lymphocyte caspase