PYPAF3, a PYRIN-containing APAF-1-like protein, is a feedback regulator of caspase-1-dependent interleukin-1β secretion
PYPAF3, a PYRIN-containing APAF-1-like protein, is a feedback regulator of caspase-1-dependent interleukin-1β secretion
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DOI：
10.1074/jbc.m410057200
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发表时间：
2005-06-10
影响因子：
4.8
通讯作者：
Suda, T
中科院分区：
文献类型：
--
作者：
Kinoshita, T;Wang, YT;Suda, T
PYPAF3是含有pyrin的凋亡蛋白酶激活因子-1样蛋白（PYPAFs，也称为NALPs）的成员。在该家族的成员中，PYPAF1、PYPAF5、PYPAF7和NALP1已被证明在接头分子ASC存在下诱导caspase-1依赖性白细胞介素-1 β分泌和NF-kappa B活化。另一方面，我们最近发现PYNOD，这个家族的另一个成员，是这些反应的抑制因子。在这里，我们发现PYPAF3是第二个抑制caspase-1依赖性白细胞介素-1 β分泌的成员。相比之下，PYPAF2/NALP2不抑制这种反应，而是抑制由PYPAF1和ASC联合表达诱导的NF-kappa B激活。PYPAF2和PYPAF3 mrna在多种组织中广泛表达；然而，这两种基因在骨骼肌中都不表达，只有pypaf2mrna在心脏和大脑中表达。它们也在许多造血和非造血细胞系中表达。脂多糖或白细胞介素-1 β刺激单核THP-1细胞诱导pypaf3mrna表达。此外，PYPAF3在THP-1细胞中的稳定表达使细胞对脂多糖产生白细胞介素-1 β的能力丧失。这些结果表明PYPAF3是白细胞介素-1 β分泌的反馈调节因子。因此，PYPAF2、PYPAF3与PYNOD共同构成PYPAFs的一个抗炎亚群。
PYPAF3 is a member of the PYRIN-containing apoptotic protease-activating factor-1-like proteins (PYPAFs, also called NALPs). Among the members of this family, PYPAF1, PYPAF5, PYPAF7, and NALP1 have been shown to induce caspase-1-dependent interleukin-1 beta secretion and NF-kappa B activation in the presence of the adaptor molecule ASC. On the other hand, we recently discovered that PYNOD, another member of this family, is a suppressor of these responses. Here, we show that PYPAF3 is the second member that inhibits caspase-1-dependent interleukin-1 beta secretion. In contrast, PYPAF2/NALP2 does not inhibit this response but rather inhibits the NF-kappa B activation that is induced by the combined expression of PYPAF1 and ASC. Both PYPAF2 and PYPAF3 mRNAs are broadly expressed in a variety of tissues; however, neither is expressed in skeletal muscle, and only PYPAF2 mRNA is expressed in heart and brain. They are also expressed in many cell lines of both hematopoietic and non-hematopoietic lineages. Stimulation of monocytic THP-1 cells with lipopolysaccharide or interleukin-1 beta induced PYPAF3 mRNA expression. Furthermore, the stable expression of PYPAF3 in THP-1 cells abrogated the ability of the cells to produce interleukin-1 beta in response to lipopolysaccharide. These results suggest that PYPAF3 is a feedback regulator of interleukin-1 beta secretion. Thus, PYPAF2 and PYPAF3, together with PYNOD, constitute an anti-inflammatory subgroup of PYPAFs.