Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants
Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants
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DOI：
10.1016/j.molcel.2007.08.029
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发表时间：
2007-10-26
期刊：
影响因子：
16
通讯作者：
Alnemri, Emad S.
中科院分区：
文献类型：
--
作者：
Yu, Je-Wook;Fernandes-Alnemri, Teresa;Alnemri, Emad S.
细胞骨架组织蛋白PSTPIP 1突变导致自身炎症性PAPA综合征的分子机制仍然是难以捉摸的。在这里，我们证明，PSTPIP 1需要家族性地中海热蛋白pyrin组装的ASC pyroptosome，一个分子平台，招募和激活caspase-1。我们提供的证据表明，pyrin是PSTPIP 1的胞质受体。由于Pyrin结构域（PYD）和B-box之间的分子内相互作用，Pyrin以同源三聚体的形式存在于自抑制状态。PSTPIP 1也是一种同源三聚体，PSTPIP 1的连接通过暴露其PYD来激活pyrin，从而使其与ASC相互作用并促进ASC寡聚化成活性ASC焦磷酸酶体。由于它们对pyrin的B盒PAPA相关PSTPIP 1突变体的高结合亲和力，发现它们在诱导pyrin活化方面比WT PSTPIP 1更有效。因此，组成性连接和激活pyrin突变PSTPIP 1蛋白解释了自身炎症表型中看到的PAPA综合征。
The molecular mechanism by which mutations in the cytos keleton-organizing protein PSTPIP1 cause the autoinflammatory PAPA syndrome is still elusive. Here, we demonstrate that PSTPIP1 requires the familial Mediterranean fever protein pyrin to assemble the ASC pyroptosome, a molecular platform that recruits and activates caspase-1. We provide evidence that pyrin is a cytosolic receptor for PSTPIP1. Pyrin exists as a homotrimer in an autoinhibited state due to intramolecular interactions between its pyrin domain (PYD) and B-box. Ligation by PSTPIP1, which is also a homotrimer, activates pyrin by unmasking its PYD, thereby allowing it to interact with ASC and facilitate ASC oligomerization into an active ASC pyroptosome. Because of their high binding affinity to pyrin's B-box PAPA-associated PSTPIP1 mutants were found to be more effective than WT PSTPIP1 in inducing pyrin activation. Therefore, constitutive ligation and activation of pyrin by mutant PSTPIP1 proteins explain the autoinflammatory phenotype seen in PAPA syndrome.