| First Author | Hashiramoto A | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 6 | Pages | 1933-1943 |
| PubMed ID | 29180447 | Mgi Jnum | J:258372 |
| Mgi Id | MGI:6117506 | Doi | 10.1074/jbc.M117.798884 |
| Citation | Hashiramoto A, et al. (2018) A variant of death-receptor 3 associated with rheumatoid arthritis interferes with apoptosis-induction of T cell. J Biol Chem 293(6):1933-1943 |
| abstractText | 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. |
