2010年10月4日,，北京生命科學(xué)研究所王曉晨博士實驗室在Proc. Natl. Acad. Sci. USA雜志在線發(fā)表題為“Sequential action of Caenorhabditis elegans Rab GTPases regulates phagolysosome formation during apoptotic cell degradation”的文章。該文章報道了線蟲RAB-2,RAB-7和RAB-14在凋亡細(xì)胞降解過程中的順序作用。
在細(xì)胞凋亡后,，凋亡細(xì)胞會被臨近細(xì)胞或?qū)ｉT的吞噬細(xì)胞識別并吞噬降解。目前,，關(guān)于已被吞噬的凋亡細(xì)胞如何被降解的分子機制仍知之甚少,。通過遺傳學(xué)、分子生物學(xué)等實驗方法王曉晨實驗室在線蟲中克隆得到了基因rab-14,，它是人類基因Rab GTPase 14在線蟲中的同源基因,。研究首先發(fā)現(xiàn)該基因與凋亡細(xì)胞的降解過程有關(guān)。rab-14在線蟲的吞噬細(xì)胞中起作用,它與另外一個之前由王曉晨實驗室和Dr. Zheng Zhou實驗室同時發(fā)現(xiàn)的Rab GTPase 2/UNC-108并行作用,，共同調(diào)節(jié)吞噬小體的酸化,。另外,，RAB-14和UNC-108還與RAB GTPase 7一起調(diào)節(jié)吞噬小體與溶酶體的融合過程。RAB-14和UNC-108并行作用,，先介導(dǎo)溶酶體附著到吞噬小體表面,，隨后RAB-7介導(dǎo)附著的溶酶體膜泡與吞噬小體融合，并最終降解凋亡細(xì)胞,。
凋亡細(xì)胞的吞噬降解過程是整個細(xì)胞死亡程序中必不可少的一環(huán),，對死亡細(xì)胞清除的障礙會引起諸如哮喘、類風(fēng)濕性關(guān)節(jié)炎和狼瘡等炎癥疾病和自身免疫紊亂,。迄今為止,，關(guān)于吞噬小體的形成和成熟以及凋亡細(xì)胞的降解過程已有一些報道，但具體機制仍不清楚,。王曉晨實驗室發(fā)現(xiàn)了rab-14基因?qū)ι鲜鲞^程起調(diào)節(jié)作用,，并且研究了與另外兩個已知基因unc-108和rab-7的相互關(guān)系。最后,，本文研究證實小鼠的Rab14在凋亡細(xì)胞的清除過程中可以替代線蟲RAB-14的功能,，它在降解凋亡細(xì)胞的功能在哺乳動物中是保守的。
郭鵬飛, 胡天婧為本文的共同第一作者,，參與此工作的還有張娟,，姜善雅。NIBS研究員王曉晨博士是本文的通訊作者,。此項研究為科技部863和北京市科委資助課題,，在北京生命科學(xué)研究所完成。（生物谷Bioon.com）
生物谷推薦英文摘要：
PNAS doi: 10.1073/pnas.1008946107
Sequential action of Caenorhabditis elegans Rab GTPases regulates phagolysosome formation during apoptotic cell degradation
Pengfei Guoa,b,1, Tianjing Hub,1, Juan Zhangb, Shanya Jiangb, and Xiaochen Wangb,2
aSchool of Life Sciences, Peking University, Beijing 100871, China; and
bNational Institute of Biological Sciences, Beijing 102206, China
Phagocytosis of apoptotic cells requires recognition of cell corpses followed by internalization and enclosure within plasma membrane-derived phagosomes. Phagosomes undergo maturation to generate phagolysosomes in which cell corpses are degraded; however, regulation of the maturation process is poorly understood. Here, we identified Rab GTPase 14, which regulates apoptotic cell degradation in Caenorhabditis elegans. rab-14 mutants accumulate many persistent cell corpses owing to defective cell corpse clearance. Loss of rab-14 function affects several steps of phagosome maturation including phagosomal acidification and phagolysosome formation. RAB-14 and UNC-108/RAB2 are recruited to phagosomes at a similar stage and function redundantly to regulate phagosome maturation. Three Rabs, RAB-14, UNC-108/RAB2, and RAB-7, act in sequential steps to control phagolysosome formation. RAB-14 and UNC-108 recruit lysosomes, whereas RAB-7 mediates fusion of lysosomes to phagosomes. Our data reveal the sequential action of Rab GTPases in regulating tethering, docking, and fusion of lysosomes to apoptotic cell-containing phagosomes.
