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

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.

• Authors: Akira Hashiramoto, Yoshitake Konishi, Koichi Murayama, Hiroki Kawasaki, Kohsuke Yoshida, Ken Tsumiyama, Kimie Tanaka, Masaru Mizuhara, Toshio Shiotsuki, Hitomi Kitamura, Koichiro Komai, Tomoatsu Kimura, Hideo Yagita, Kazuko Shiozawa, Shunichi Shiozawa
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 293 Issue 6 Pg. 1933-1943 (02 09 2018) ISSN: 1083-351X [Electronic] United States
• PMID: 29180447 (Publication Type: Journal Article)
• Copyright: © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Receptors, Tumor Necrosis Factor, Member 25
• TNFRSF25 protein, human
• Tnfsf15 protein, mouse
• Tumor Necrosis Factor Ligand Superfamily Member 15

Topics

• Animals
• Apoptosis
• Arthritis, Rheumatoid (physiopathology)
• Exons
• Humans
• Introns
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Polymorphism, Single Nucleotide
• Protein Domains
• Receptors, Tumor Necrosis Factor, Member 25 (chemistry, genetics, metabolism)
• Signal Transduction
• T-Lymphocytes (cytology, metabolism)
• Tumor Necrosis Factor Ligand Superfamily Member 15 (genetics, metabolism)