Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO
Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO
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DOI：
10.1016/j.cub.2004.12.029
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发表时间：
2004-12-29
期刊：
影响因子：
9.2
通讯作者：
Ravichandran, KS
中科院分区：
文献类型：
--
作者：
DeBakker, CD;Haney, LB;Ravichandran, KS
背景：经历凋亡的细胞的吞噬作用在发育、细胞更新和伤口愈合过程中至关重要。未能及时清除凋亡细胞与自身免疫性疾病有关。线虫 CED-12 和哺乳动物 ELMO 是进化上保守的支架蛋白，在从蠕虫到人类的吞噬过程中发挥着关键作用。 ELMO 与 Dock180（Rac 的鸟嘌呤核苷酸交换因子）一起发挥作用，在吞噬和细胞迁移过程中介导 Rac 依赖性细胞骨架重组。然而，吞噬过程中 ELMO 和 Dock180 上游的组件仍然难以捉摸。结果：在这里，我们定义了一个涉及小 GTPase RhoG 及其交换因子 TRIO 的保守信号模块，该模块在吞噬过程中在 ELMO/Dock180/Rac 上游发挥作用。对秀丽隐杆线虫的补充研究表明，MIG-2（我们将其鉴定为哺乳动物 RhoG 的同源物）和 UNC-73（TRIO 同源物）也调节 CED-12 上游的体内尸体清除。在分子水平上，我们在 CED-12/ELMO 中鉴定了一组新的进化保守的犰狳 (ARM) 重复序列，可介导与激活的 MIG-2/RhoG 的相互作用；这反过来又促进了 Dock180 介导的 Rac 激活和细胞骨架重组。结论：本文介绍的体外和体内研究相结合，确定了吞噬过程中两个进化上保守的参与者：TRIO/UNC73 和 RhoG/MIG-2，并且 TRIO -> RhoG 信号模块通过 ELMO/CED-12 与吞噬过程中依赖于 Dock180 的 Rac 激活相关联。这项工作还确定了 CED-12/ELMO 中的 ARM 重复序列及其在连接 RhoG 和 Rac（两种在吞噬过程中协同作用的 GTP 酶）中的作用。
Background: Phagocytosis of cells undergoing apoptosis is essential during development, cellular turnover, and wound healing. Failure to promptly clear apoptotic cells has been linked to autoimmune disorders. C. elegans CED-12 and mammalian ELMO are evolutionarily conserved scaffolding proteins that play a critical role in engulfment from worm to human. ELMO functions together with Dock180 (a guanine nucleotide exchange factor for Rac) to mediate Rac-dependent cytoskeletal reorganization during engulfment and cell migration. However, the components upstream of ELMO and Dock180 during engulfment remain elusive.Results: Here, we define a conserved signaling module involving the small GTPase RhoG and its exchange factor TRIO, which functions upstream of ELMO/Dock180/ Rac during engulfment. Complementary studies in C. elegans show that MIG-2 (which we identify as the homolog of mammalian RhoG) and UNC-73 (the TRIO homolog) also regulate corpse clearance in vivo, upstream of CED-12. At the molecular level, we identify a novel set of evolutionarily conserved Armadillo (ARM) repeats within CED-12/ELMO that mediate an interaction with activated MIG-2/RhoG; this, in turn, promotes Dock180-mediated Rac activation and cytoskeletal reorganization.Conclusions: The combination of in vitro and in vivo studies presented here identify two evolutionarily conserved players in engulfment, TRIO/UNC73 and RhoG/ MIG-2, and the TRIO --> RhoG signaling module is linked by ELMO/CED-12 to Dock180-dependent Rac activation during engulfment. This work also identifies ARM repeats within CED-12/ELMO and their role in linking RhoG and Rac, two GTPases that function in tandem during engulfment.