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

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

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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.

Original languageEnglish
Pages (from-to)1933-1943
Number of pages11
JournalJournal of Biological Chemistry
Volume293
Issue number6
DOIs
Publication statusPublished - Jan 1 2018

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Receptors, Tumor Necrosis Factor, Member 25
T-cells
Rheumatoid Arthritis
Apoptosis
T-Lymphocytes
Introns
Ligands
Nucleotides
Genes
Protein Splicing
Granulocyte Precursor Cells
Lymphocytes
Nonsense Codon
RNA Precursors
Polymorphism
DNA Sequence Analysis
Transgenic Mice
Arthritis
Single Nucleotide Polymorphism
Exons

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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

A variant of death-receptor 3 associated with rheumatoid arthritis interferes with apoptosis-induction of T cell. / Hashiramoto, Akira; Konishi, Yoshitake; Murayama, Koichi; Kawasaki, Hiroki; Yoshida, Kohsuke; Tsumiyama, Ken; Tanaka, Kimie; Mizuhara, Masaru; Shiotsuki, Toshio; Kitamura, Hitomi; Komai, Koichiro; Kimura, Tomoatsu; Yagita, Hideo; Shiozawa, Kazuko; Shiozawa, Shunichi.

In: Journal of Biological Chemistry, Vol. 293, No. 6, 01.01.2018, p. 1933-1943.

Research output: Contribution to journalArticle

Hashiramoto, A, Konishi, Y, Murayama, K, Kawasaki, H, Yoshida, K, Tsumiyama, K, Tanaka, K, Mizuhara, M, Shiotsuki, T, Kitamura, H, Komai, K, Kimura, T, Yagita, H, Shiozawa, 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, vol. 293, no. 6, pp. 1933-1943. https://doi.org/10.1074/jbc.M117.798884
Hashiramoto, Akira ; Konishi, Yoshitake ; Murayama, Koichi ; Kawasaki, Hiroki ; Yoshida, Kohsuke ; Tsumiyama, Ken ; Tanaka, Kimie ; Mizuhara, Masaru ; Shiotsuki, Toshio ; Kitamura, Hitomi ; Komai, Koichiro ; Kimura, Tomoatsu ; Yagita, Hideo ; Shiozawa, Kazuko ; Shiozawa, Shunichi. / A variant of death-receptor 3 associated with rheumatoid arthritis interferes with apoptosis-induction of T cell. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 6. pp. 1933-1943.
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