A variant of death-receptor 3 associated with rheumatoid arthritis interferes with apoptosis-induction of T cell.
A variant of death-receptor 3 associated with rheumatoid arthritis interferes with apoptosis-induction of T cell.
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DOI：
10.1074/jbc.m117.798884
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发表时间：
2018-02-09
期刊：
影响因子：
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通讯作者：
Shiozawa S
中科院分区：
文献类型：
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作者：
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
风湿性关节炎（RA）是一种病因不明的慢性多发性关节炎。为了阐明RA的分子机制，我们对RA患者进行了靶向DNA测序分析。该分析确定了死亡受体3（DR3）基因的变体，该基因是凋亡诱导Fas基因家族的成员，其包含4个单核苷酸多态性（SNP）和外显子5和内含子5内的14个核苷酸缺失。我们发现该缺失导致剪接调节蛋白与DR3前mRNA内含子5结合，导致内含子5的一部分成为编码序列的一部分，从而产生提前终止密码子。我们还发现，这种截短的DR3蛋白产物缺乏死亡结构域，并与野生型DR3形成异源三聚体复合物，其显性负抑制淋巴细胞中配体诱导的凋亡。转基因小鼠的骨髓细胞表达人DR3变体产生可溶性截短DR3，与TNF样配体1A（TL1A）形成复合物，抑制凋亡诱导。总之，我们的研究结果表明，DR3剪接变异体干扰配体诱导的T细胞反应和凋亡可能有助于RA的发病机制。
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.