The functional haplotype of peptidylarginine deiminase IV (S55G, A82V and A112G) associated with susceptibility to rheumatoid arthritis dominates apoptosis of acute T leukemia Jurkat cells
The functional haplotype of peptidylarginine deiminase IV (S55G, A82V and A112G) associated with susceptibility to rheumatoid arthritis dominates apoptosis of acute T leukemia Jurkat cells
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DOI：
10.1007/s10495-006-0005-0
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发表时间：
2007-03-01
期刊：
影响因子：
7.2
通讯作者：
Liu, Guang-Yaw
中科院分区：
文献类型：
--
作者：
Hung, Hui-Chih;Lin, Chien-Yu;Liu, Guang-Yaw
肽基精氨酸脱亚胺酶IV(PADI4)翻译后将肽基精氨酸转化为瓜氨酸。它在免疫细胞分化和凋亡中起着重要作用。PADI4的单核苷酸多态(SNPs)单倍型与类风湿性关节炎(RA)基因功能相关。它可以提高酶活性，导致瓜氨酸蛋白水平升高，并刺激自身抗体。此前，我们的研究表明，可诱导的PADI4会导致造血细胞死亡。在此，我们进一步研究了RA是否与PADI4单倍型(SNP PADI4；S55G、A82V和A112G)以及其酶活性的增加诱导细胞凋亡有关。在四环素(Tet)诱导的Jurkat T细胞中，离子霉素(Ion)单独作用不能诱导细胞凋亡，但能促进诱导型PADI4降低细胞存活率，促进细胞凋亡。通过体外和体内PADI酶活性测定，我们证明SNP PADI4的PADI4酶活性高于RA非危险PADI4单倍型(WT PADI4)。SNP PADI4诱导的细胞凋亡作用优于WT PADI4。此外，还比较了离子和SNP PADI4与离子和WT PADI4协同诱导细胞凋亡的作用。同时，在离子处理诱导的条件诱导型SNP PADI4细胞中，不仅Bclxl的表达下调，Bax的表达上调，而且细胞色素c从线粒体大量释放到细胞质。Western blotting数据显示，在离子处理后的可诱导SNP PADI4细胞程序性死亡过程中，凋亡体caspase活性增加。这些数据表明，SNP PADI4增加其酶活性可通过线粒体途径促进细胞凋亡，并进一步为RA的SNPs中PADI4活性上调后的发病机制提供了可能的解释。
Peptidylarginine deiminase IV (PADI4) posttranslationally converts peptidylarginine to citrulline. It plays an essential role in immune cell differentiation and apoptosis. A haplotype of single-nucleotide polymorphisms (SNPs) in PADI4 is functionally relevant as a rheumatoid arthritis (RA) gene. It could increase enzyme activity leading to raised levels of citrullinated protein and stimulating autoantibody. Previously, our study showed that inducible PADI4 causes haematopoietic cell death. Herein, we further investigate whether RA risk PADI4 haplotype (SNP PADI4; S55G, A82V and A112G) and the increase of its enzymatic activity induce apoptosis. In the tetracycline (Tet)-On Jurkat T cells, ionomycin (Ion) only treatment didn't induce apoptosis however it promoted inducible PADI4-decreased cell viability and -enhanced apoptosis. Through in vitro and in vivo PADI enzyme activity assay, we demonstrated that PADI4 enzyme activity of SNP PADI4 was higher than RA non-risk PADI4 haplotype (WT PADI4). The effect of SNP PADI4-induced apoptosis was superior to WT PADI4. In addition, both Ion and SNP PADI4 synergistically provoked apoptosis were compared with both Ion and WT PADI4. Concurrently, in the conditionally inducible SNP PADI4 cells of Ion treatment-induced apoptosis, not only the expression of Bcl-xL was down-regulated and Bax up-regulated, but also cytochrome c was released from mitochondria to cytoplasm in significant amounts. Western blotting data showed the increase in apoptosomal caspase activation during programmed cell death in the inducible SNP PADI4 cells subsequent to Ion treatment. These data demonstrated that both SNP PADI4 increasing their enzyme activity could enhance apoptosis through the mitochondrial pathway and further provide a conceivable explanation in the pathogenesis of RA following the upregulation of PADI4 activity in its SNPs.