2010年10月4日，北京生命科学研究所王晓晨博士实验室在Proc. Natl. Acad. Sci. USA杂志在线发表题为“Sequential action of Caenorhabditis elegans Rab GTPases regulates phagolysosome formation during apoptotic cell degradation”的文章。该文章报道了线虫RAB-2,RAB-7和RAB-14在凋亡细胞降解过程中的顺序作用。
在细胞凋亡后，凋亡细胞会被临近细胞或专门的吞噬细胞识别并吞噬降解。目前，关于已被吞噬的凋亡细胞如何被降解的分子机制仍知之甚少。通过遗传学、分子生物学等实验方法王晓晨实验室在线虫中克隆得到了基因rab-14，它是人类基因Rab GTPase 14在线虫中的同源基因。研究首先发现该基因与凋亡细胞的降解过程有关。rab-14在线虫的吞噬细胞中起作用,它与另外一个之前由王晓晨实验室和Dr. Zheng Zhou实验室同时发现的Rab GTPase 2/UNC-108并行作用，共同调节吞噬小体的酸化。另外，RAB-14和UNC-108还与RAB GTPase 7一起调节吞噬小体与溶酶体的融合过程。RAB-14和UNC-108并行作用，先介导溶酶体附着到吞噬小体表面，随后RAB-7介导附着的溶酶体膜泡与吞噬小体融合，并最终降解凋亡细胞。
凋亡细胞的吞噬降解过程是整个细胞死亡程序中必不可少的一环，对死亡细胞清除的障碍会引起诸如哮喘、类风湿性关节炎和狼疮等炎症疾病和自身免疫紊乱。迄今为止，关于吞噬小体的形成和成熟以及凋亡细胞的降解过程已有一些报道，但具体机制仍不清楚。王晓晨实验室发现了rab-14基因对上述过程起调节作用，并且研究了与另外两个已知基因unc-108和rab-7的相互关系。最后，本文研究证实小鼠的Rab14在凋亡细胞的清除过程中可以替代线虫RAB-14的功能，它在降解凋亡细胞的功能在哺乳动物中是保守的。
郭鹏飞, 胡天婧为本文的共同第一作者，参与此工作的还有张娟，姜善雅。NIBS研究员王晓晨博士是本文的通讯作者。此项研究为科技部863和北京市科委资助课题，在北京生命科学研究所完成。（生物谷Bioon.com）
生物谷推荐英文摘要：
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.
