A variant of death-receptor 3 associated with rheumatoid arthritis interferes with apoptosis-induction of T cell
| Autor: | Kimie Tanaka, Kohsuke Yoshida, Shunichi Shiozawa, Masaru Mizuhara, Yoshitake Konishi, Hitomi Kitamura, Koichiro Komai, Akira Hashiramoto, Hiroki Kawasaki, Ken Tsumiyama, Koichi Murayama, Toshio Shiotsuki, Tomoatsu Kimura, Hideo Yagita, Kazuko Shiozawa |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Tumor Necrosis Factor Ligand Superfamily Member 15 death domain T cell caspase T-Lymphocytes Immunology Mice Transgenic Biology lymphocyte Biochemistry Polymorphism Single Nucleotide Arthritis Rheumatoid 03 medical and health sciences Exon Mice 0302 clinical medicine Protein Domains medicine Animals Humans Molecular Biology Gene Receptors Tumor Necrosis Factor Member 25 Death domain Alternative splicing Intron apoptosis Cell Biology Exons Molecular biology Introns Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure arthritis Apoptosis Death receptor 3 030215 immunology Signal Transduction |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|