Pyrin, product of the MEFV locus, interacts with the proapoptotic protein, Siva
Pyrin, product of the MEFV locus, interacts with the proapoptotic protein, Siva
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DOI：
10.1002/jcp.21435
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发表时间：
2008-09-01
影响因子：
5.6
通讯作者：
Gumucio, Deborah L.
中科院分区：
文献类型：
--
作者：
Balci-Peynircioglu, Banu;Waite, Andrea L.;Gumucio, Deborah L.
pyrin突变导致自身炎症性疾病家族性地中海热（FMF），这是一种以散发性和不可预测的发热和局部剧烈疼痛为特征的综合征。目前，尚不清楚攻击是如何引发的，也不清楚为什么它们会在两三天后自发解决。事实上，pyrin蛋白的细胞功能及其在FMF中功能障碍的分子基础迄今尚未明确定义。鉴定pyrin相互作用蛋白有可能增加我们对pyrin功能的细胞网络的理解。先前的报道已经确定，pyrin与凋亡蛋白ASC、细胞骨架衔接蛋白PSTPIP 1、炎性半胱天冬酶、半胱天冬酶-I和某些形式的胞质锚定蛋白14-3-3相互作用。在这里，我们报告说，pyrin也与Siva，促凋亡蛋白的相互作用，首先确定其与CD 27，TNF家族受体的胞质尾部。pyrin和Siva之间的相互作用涉及pyrin的C-末端B30.2/rfp/SRPY结构域和Siva的外显子I。我们表明，湿婆和pyrin确实共同表达在人类中性粒细胞，单核细胞，滑膜细胞。此外，使用一种新的蛋白质/蛋白质相互作用测定，我们证明，pyrin可以招募Siva的ASC斑点，建立一个潜在的平台，ASC和Siva功能的交叉。最后，我们表明，pyrin调制氧化应激介导的湿婆细胞凋亡反应。因此，Siva-pyrin相互作用可能是未来治疗策略的潜在靶点。
Mutations in pyrin cause the autoinflammatory disorder familial Mediterranean fever (FMF), a syndrome characterized by sporadic and unpredictable attacks of fever and localized severe pain. Currently, it is not clear how attacks are triggered, nor why they spontaneously resolve after 2 or 3 days. In fact, the cellular function of the pyrin protein and the molecular underpinnings of its malfunction in FMF have so far eluded clear definition. The identification of pyrin-interacting proteins has the potential to increase our understanding of the cellular networks in which pyrin functions. Previous reports have established that pyrin interacts with the apoptotic protein ASC, the cytoskeletal adaptor protein PSTPIP 1, the inflammatory caspase, Caspase-I and certain forms of the cytosolic anchoring protein 14-3-3. Here, we report that pyrin also interacts with Siva, a pro-apoptotic protein first identified for its interaction with the cytosolic tail of CD27, a TNF family receptor. The interaction between pyrin and Siva involves the C-terminal B30.2/rfp/SRPY domain of pyrin and exon I of Siva. We show that Siva and pyrin are indeed co-expressed in human neutrophils, monocytes, and synovial cells. Furthermore, using a novel protein/protein interaction assay, we demonstrate that pyrin can recruit Siva to ASC specks, establishing a potential platform for intersection of ASC and Siva function. Finally, we show that pyrin modulates the apoptotic response to oxidative stress mediated by Siva. Thus, the Siva-pyrin interaction may be a potential target for future therapeutic strategies.