Thioredoxin Increases Exocytosis by Denitrosylating N-Ethylmaleimide-sensitive Factor
Thioredoxin Increases Exocytosis by Denitrosylating N-Ethylmaleimide-sensitive Factor
复制标题
DOI：
10.1074/jbc.m110.201780
复制
发表时间：
2011-04-01
影响因子：
4.8
通讯作者：
Lowenstein, Charles J.
中科院分区：
文献类型：
--
作者：
Ito, Takashi;Yamakuchi, Munekazu;Lowenstein, Charles J.
胞吐作用涉及颗粒和质膜之间的膜融合。一氧化氮（NO）通过化学修饰N-乙基马来酰亚胺敏感因子（NSF）抑制胞吐作用，NSF是胞吐机制的关键组分。然而，细胞通过未知的机制在暴露于NO的数小时内恢复释放信使分子的能力。我们现在确定硫氧还蛋白（TRX 1）作为一种去亚硝基化酶，逆转一氧化氮抑制胞吐。内源性合成的NO增加S-亚硝基化的NSF水平，但S-亚硝基化的NSF水平在暴露于NO后3小时内下降。我们发现，NO增加TRX 1和NSF之间的相互作用，和内源性TRX 1从S-亚硝基化的NSF中去除NO。TRX 1的敲低增加S-亚硝基化NSF的水平，抑制胞吐作用，并抑制白细胞粘附。总之，这些数据表明TRX 1通过使NSF去亚硝基化来促进胞吐作用。我们的研究结果表明，TRX 1可能在各种生理环境中调节胞吐作用，如血管炎症，血栓形成和胰岛素释放。
Exocytosis involves membrane fusion between granules and the plasma membrane. Nitric oxide (NO) inhibits exocytosis by chemically modifying N-ethylmaleimide-sensitive factor (NSF), a key component of the exocytic machinery. However, cells recover the ability to release messenger molecules within hours of exposure to NO through unknown mechanisms. We now identify thioredoxin (TRX1) as a denitrosylase that reverses NO inhibition of exocytosis. Endogenously synthesized NO increases S-nitrosylated NSF levels, but S-nitrosylated NSF levels decrease within 3 h after exposure to NO. We found that NO increases the interaction between TRX1 and NSF, and endogenous TRX1 removes NO from S-nitrosylated NSF. Knockdown of TRX1 increases the level of S-nitrosylated NSF, prolongs the inhibition of exocytosis, and suppresses leukocyte adhesion. Taken together, these data show that TRX1 promotes exocytosis by denitrosylating NSF. Our findings suggest that TRX1 might regulate exocytosis in a variety of physiological settings, such as vascular inflammation, thrombosis, and insulin release.