Geranylgeraniol regulates negatively caspase-1 autoprocessing:: Implication in the Th1 response against Mycobacterium tuberculosis
Geranylgeraniol regulates negatively caspase-1 autoprocessing:: Implication in the Th1 response against Mycobacterium tuberculosis
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DOI：
10.4049/jimmunol.173.8.4936
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发表时间：
2004-10-15
影响因子：
4.4
通讯作者：
Lasunción, MA
中科院分区：
文献类型：
--
作者：
Montero, MT;Matilla, J;Lasunción, MA
Caspase-1是一种半胱氨酸蛋白酶，由两个20-kDa和两个10-kDa亚基组成，可将pro-IL-1 β和pro-IL-18加工成成熟形式。这种酶作为潜伏酶原存在于细胞中，通过严格调节的蛋白水解级联反应变得活跃。激活是由衔接分子的寡聚化或由称为炎性体的多蛋白复合物的形成引发的。与衔接分子或炎性小体形成竞争的蛋白质对胱天蛋白酶-1活化起负调节作用。我们之前报道过氟伐他汀（3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂）可以增加PBMC中半胱天冬酶-1的活性。结核分枝杆菌加强了这种作用，使IL-1 β、IL-18和IFN-γ的产生加剧。甲羟戊酸是3-羟基-3-甲基戊二酰辅酶A还原酶的产物，是非固醇类异戊二烯和固醇形成的前体。在这项研究中，我们研究了参与甲羟戊酸衍生物的caspase-1激活的调节。SKF-104976或氟哌啶醇抑制甾醇形成对IL-1 β释放无影响。然而，类异戊二烯香叶基香叶醇阻止半胱天冬酶-1激活和氟伐他汀诱导的IL产生加剧。即使在没有氟伐他汀的情况下，这种类异戊二烯也显著减少了用分枝杆菌处理的PBMC释放IL-18和IFN-γ。与caspase-1活性增加相关，氟伐他汀刺激前体裂解，增强活性亚基p10的形成。香叶基香叶醇不仅阻止这种作用，但诱导前体积累。目前的研究结果表明，一旦蛋白水解级联反应启动，香叶基香叶醇可能会施加额外的负调控caspase-1的切割过程。
Caspase-1 is a cysteine protease composed by two 20-kDa and two 10-kDa subunits that processes pro-IL-1beta and pro-IL-18 to their mature forms. This enzyme is present in cells as a latent zymogen that becomes active through a tightly regulated proteolytic cascade. Activation is initiated by the oligomerization of an adaptor molecule, or by the formation of a multiprotein complex named inflammasome. Negative regulation of caspase-1 activation is exerted by proteins that compete with the adaptor molecule or with the inflammasome formation. We previously reported that fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, increases caspase-1 activity in PBMC. This effect was strengthened by Mycobacterium tuberculosis, rending an exacerbated IL-1beta, IL-18, and IFN-gamma production. Mevalonate, the product of 3-hydroxy-3-methylglutaryl coenzyme A reductase, is a precursor for both nonsterol isoprenoid and sterol formation. In this study, we studied the involvement of mevalonate derivatives in the regulation of caspase-1 activation. Inhibition of sterol formation by SKF-104976 or haloperidol had no effect on IL-1beta release. However, the isoprenoid geranylgeraniol prevented both caspase-1 activation and the exacerbated IL production induced by fluvastatin. This isoprenoid significantly reduced the release of IL-18 and IFN-gamma by PBMC treated with mycobacteria, even in the absence of fluvastatin. In correlation with the increased caspase-1 activity, fluvastatin stimulated the proforms cleavage, enhancing the formation of active subunit p10. Geranylgeraniol not only prevented this effect, but induced proforms accumulation. Present results suggest that, once the proteolytic cascade is initiated, geranylgeraniol may exert an additional negative regulation on caspase-1 cleavage process.