Extracellular ATP induces unconventional release of glyceraldehyde-3-phosphate dehydrogenase from microglial cells
Extracellular ATP induces unconventional release of glyceraldehyde-3-phosphate dehydrogenase from microglial cells
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DOI：
10.1016/j.imlet.2015.08.002
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发表时间：
2015-10-01
影响因子：
4.4
通讯作者：
Kitani, Hiroshi
中科院分区：
文献类型：
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作者：
Takenouchi, Takato;Tsukimoto, Mitsutoshi;Kitani, Hiroshi
甘油醛-3-磷酸脱氢酶（GAPDH）是主要定位于细胞质中的关键糖酵解酶。然而，最近的研究表明，GAPDH由各种细胞释放，并且细胞外GAPDH参与神经元细胞中轴突发生的调节。也有报道GAPDH在巨噬细胞表面表达并作为转铁蛋白受体发挥功能。然而，由于GAPDH是一种无前导蛋白，其到达细胞外环境的机制仍不清楚。在这里，我们研究了P2 X7受体（P2 X7 R），一种ATP门控阳离子通道，在GAPDH从小胶质细胞（大脑中的常驻巨噬细胞）的非常规释放中的作用。ATP激活P2 X7 R触发了脂多糖（LPS）引发的小胶质细胞释放GAPDH。ATP诱导的微囊泡形成，外泌体释放，和K+流出，随后半胱天冬酶-1激活可能参与GAPDH释放，但ATP诱导的膜孔扩张和溶酶体胞吐不是。还证明了外源GAPDH促进小胶质细胞中LPS诱导的p38 MAP激酶的磷酸化。提示P2 X7 R在小胶质细胞非常规释放GAPDH中起重要作用，释放到细胞外间隙的GAPDH可能参与脑内神经炎症反应的调节。(C)2015作者由Elsevier B. V.代表欧洲免疫学会联合会出版。
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme that is predominantly localized in the cytoplasm. However, recent studies have suggested that GAPDH is released by various cells and that extracellular GAPDH is involved in the regulation of neuritogenesis in neuronal cells. It has also been reported that GAPDH is expressed on the surfaces of macrophages and functions as a transferrin receptor. However, since GAPDH is a leaderless protein the mechanisms by which it reaches the extracellular environment remain unclear. Here, we examined the role of P2X7 receptor (P2X7R), an ATP-gated cation channel, in the unconventional release of GAPDH from microglial cells, the resident macrophages in the brain. The activation of P2X7R by ATP triggered GAPDH release from lipopolysaccharide (LPS)-primed microglial cells. ATP-induced microvesicle formation, exosome release, and K+ efflux followed by caspase-1 activation are likely involved in the GAPDH release, but ATP-induced dilatation of membrane pores and lysosome exocytosis are not. It was also demonstrated that exogenous GAPDH facilitated LPS-induced phosphorylation of p38 MAP kinase in microglial cells. These findings suggest that P2X7R plays an important role in the unconventional release of GAPDH from microglial cells, and the GAPDH released into the extracellular space might be involved in the regulation of the neuroinflammatory response in the brain. (C) 2015 The Authors. Published by Elsevier B.V. on behalf of European Federation of Immunological Societies.