Secretogranin III directs secretory vesicle biogenesis in mast cells in a manner dependent upon interaction with chromogranin A
Secretogranin III directs secretory vesicle biogenesis in mast cells in a manner dependent upon interaction with chromogranin A
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DOI：
10.4049/jimmunol.181.7.5024
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发表时间：
2008-10-01
影响因子：
4.4
通讯作者：
Stokes, Alexander J.
中科院分区：
文献类型：
--
作者：
Prasad, Prerna;Yanagihara, Angel A.;Stokes, Alexander J.
肥大细胞是驻留在身体屏障组织中的颗粒免疫细胞。这些细胞协调炎症反应。促炎介质储存在肥大细胞胞浆内的颗粒状结构中。控制肥大细胞颗粒的胞吐是变态反应性和炎症性疾病的主要治疗目标。然而，肥大细胞中控制颗粒生物发生和丰度的蛋白质还没有被阐明。在神经内分泌细胞，其致密的核心颗粒与肥大细胞颗粒惊人地相似，颗粒蛋白调节颗粒发生。我们的研究表明，分泌颗粒素III(SgIII)蛋白参与了肥大细胞分泌颗粒的生物发生。SGIII在肥大细胞中含量丰富，并被组织成泡状结构。我们的结果表明，肥大细胞中SgIII的过度表达足以导致这些细胞中颗粒室的扩张。这些新的颗粒储存了炎症介质，这些介质在生理刺激下被释放，表明它们是真正的分泌囊泡。在肥大细胞中，如在神经内分泌细胞中，我们发现SgIII与嗜铬粒蛋白A(CgA)形成复合体。当CgA与SgIII复合时，CgA具有造粒作用。我们的数据表明，SgIII(1-210)的一个新的非粒基因截断突变体缺乏与CGA相互作用的能力。因此，在肥大细胞中，CgA-SgIII复合体可能在分泌颗粒的生物发生中发挥关键作用。SGIII在肥大细胞中的功能不太可能局限于它与CGA的伙伴关系，因为我们的相互作用陷阱分析表明SGIII有多个结合伙伴，包括肥大细胞离子通道TRPA1。
Mast cells are granular immunocytes that reside in the body's barrier tissues. These cells orchestrate inflammatory responses. Proinflammatory mediators are stored in granular structures within the mast cell cytosol. Control of mast cell granule exocytosis is a major therapeutic goal for allergic and inflammatory diseases. However, the proteins that control granule biogenesis and abundance in mast cells have not been elucidated. In neuroendocrine cells, whose dense core granules are strikingly similar to mast cell granules, granin proteins regulate granulogenesis. Our studies suggest that the Secretogranin III (SgIII) protein is involved in secretory granule biogenesis in mast cells. SgIII is abundant in mast cells, and is organized into vesicular structures. Our results show that over-expression of SgIII in mast cells is sufficient to cause an expansion of a granular compartment in these cells. These novel granules store inflammatory mediators that are released in response to physiological stimuli, indicating that they function as bona fide secretory vesicles. In mast cells, as in neuroendocrine cells, we show that SgIII is complexed with Chromogranin A (CgA). CgA is granulogenic when complexed with SgIII. Our data show that a novel non-granulogenic truncation mutant of SgIII (1-210) lacks the ability to interact with CgA. Thus, in mast cells, a CgA-SgIII complex may play a key role in secretory granule biogenesis. SgIII function in mast cells is unlikely to be limited to its partnership with CgA, as our interaction trap analysis suggests that SgIII has multiple binding partners, including the mast cell ion channel TRPA1.