Proteomic and functional analysis identifies galectin-1 as a novel regulatory component of the cytotoxic granule machinery
Proteomic and functional analysis identifies galectin-1 as a novel regulatory component of the cytotoxic granule machinery
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DOI：
10.1038/cddis.2017.506
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发表时间：
2017-12-01
影响因子：
9
通讯作者：
Amarante-Mendes, Gustavo P.
中科院分区：
文献类型：
--
作者：
Clemente, Tiago;Vieira, Narcisio J.;Amarante-Mendes, Gustavo P.
细胞毒性T淋巴细胞（CTL）分泌的分泌颗粒是细胞内微生物和肿瘤细胞的有力武器。尽管取得了重大进展，但有关靶向驱动的脱粒、效应细胞存活以及裂解颗粒的组成和结构的分子机制的信息仍然有限。在这里，使用蛋白质组学的方法，我们确定了一个小组的推定细胞毒性颗粒蛋白，包括一些已知的颗粒成分和新的蛋白质，有助于调节CTL裂解机制。特别是，我们确定了半乳糖凝集素-1（Gal 1），内源性免疫调节凝集素，作为一个不可分割的组成部分的分泌颗粒机械和揭示意想不到的功能，这种凝集素在调节CTL杀伤活性。机制研究揭示了Gal 1通过影响Fas-Fas配体相互作用来控制非分泌性裂解途径的能力。这项研究提供了新的见解的细胞毒性颗粒机械的组成，突出了动态的串扰之间的分泌和非分泌途径在控制CTL裂解功能。
Secretory granules released by cytotoxic T lymphocytes (CTLs) are powerful weapons against intracellular microbes and tumor cells. Despite significant progress, there is still limited information on the molecular mechanisms implicated in target-driven degranulation, effector cell survival and composition and structure of the lytic granules. Here, using a proteomic approach we identified a panel of putative cytotoxic granule proteins, including some already known granule constituents and novel proteins that contribute to regulate the CTL lytic machinery. Particularly, we identified galectin-1 (Gal1), an endogenous immune regulatory lectin, as an integral component of the secretory granule machinery and unveil the unexpected function of this lectin in regulating CTL killing activity. Mechanistic studies revealed the ability of Gal1 to control the non-secretory lytic pathway by influencing Fas-Fas ligand interactions. This study offers new insights on the composition of the cytotoxic granule machinery, highlighting the dynamic cross talk between secretory and non-secretory pathways in controlling CTL lytic function.