細(xì)胞凋亡是發(fā)育中的一個重要環(huán)節(jié)。其中凋亡細(xì)胞的清除能防止凋亡細(xì)胞中的有害物質(zhì)外泄而傷害正常細(xì)胞,，凋亡細(xì)胞清除缺陷會導(dǎo)致炎癥和免疫紊亂,。2009年6月23日,，北京生命科學(xué)研究所王曉晨實驗室在Development雜志在線發(fā)表有關(guān)GTP水解激活蛋白TBC-2在凋亡細(xì)胞清除過程中功能的最新研究成果。
研究以線蟲為模式生物,，通過遺傳篩選獲得凋亡細(xì)胞清除異常突變體,，并將其所影響基因tbc-2克隆,，tbc-2編碼一個具有TBC結(jié)構(gòu)RAB GTPase的GAP。TBC-2具有3個結(jié)構(gòu)：PH, SMC和TBC,。根據(jù)結(jié)構(gòu)缺失分析,，表明這三個結(jié)構(gòu)對于TBC-2發(fā)揮凋亡細(xì)胞清除功能都是不可或缺的。其中SMC結(jié)構(gòu)負(fù)責(zé)將TBC-2定位在吞噬體上,。TBC-2的GAP活性的破壞會造成TBC-2徹底失去凋亡細(xì)胞清除功能,，表明TBC-2的GAP活性對于凋亡細(xì)胞降解是必須的。
研究發(fā)現(xiàn)rab-5 RNAi可以緩解tbc-2突變體中凋亡細(xì)胞降解的缺陷,，同時過表達(dá)持久激活的RAB-5也會造成類似于tbc-2突變體中凋亡細(xì)胞降解的缺陷，表明在凋亡細(xì)胞降解的過程中,，TBC-2可能調(diào)控RAB-5,。
為了進(jìn)一步了解TBC-2是如何通過調(diào)節(jié)RAB-5進(jìn)而調(diào)控凋亡細(xì)胞降解過程,，研究人員在tbc-2突變體中追蹤了RAB-5在吞噬體上的動態(tài)分布，發(fā)現(xiàn)在突變體中RAB-5從吞噬體上的釋放被延遲了,，同時發(fā)現(xiàn)吞噬體對RAB-7的募集,，吞噬體與溶酶體的融合，以及吞噬體的酸化都受到了影響,，表明TBC-2在吞噬體上可以下調(diào)RAB-5的活性，促使RAB-5從吞噬體上釋放,，進(jìn)而促進(jìn)吞噬體進(jìn)一步成熟。（生物谷Bioon.com）
生物谷推薦原始出處：
Development 136, 2445-2455 (2009) doi: 10.1242/10.1242/dev.035949
C. elegans Rab GTPase activating protein TBC-2 promotes cell corpse degradation by regulating the small GTPase RAB-5
Weida Li1,3, Wei Zou2,3, Dongfeng Zhao3, Jiacong Yan3, Zuoyan Zhu1, Jing Lu3 and Xiaochen Wang3,*
1 College of Life Science, Peking University, Beijing 100871, China.
2 College of Biological Sciences, China Agricultural University, Beijing 100094, China.
3 National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
During apoptosis, dying cells are quickly internalized by neighboring cells or phagocytes, and are enclosed in phagosomes that undergo a maturation process to generate the phagoslysosome, in which cell corpses are eventually degraded. It is not well understood how apoptotic cell degradation is regulated. Here we report the identification and characterization of the C. elegans tbc-2 gene, which is required for the efficient degradation of cell corpses. tbc-2 encodes a Rab GTPase activating protein (GAP) and its loss of function affects several events of phagosome maturation, including RAB-5 release, phosphatidylinositol 3-phosphate dynamics, phagosomal acidification, RAB-7 recruitment and lysosome incorporation, which leads to many persistent cell corpses at various developmental stages. Intriguingly, the persistent cell corpse phenotype of tbc-2 mutants can be suppressed by reducing gene expression of rab-5, and overexpression of a GTP-locked RAB-5 caused similar defects in phagosome maturation and cell corpse degradation. We propose that TBC-2 functions as a GAP to cycle RAB-5 from an active GTP-bound to an inactive GDP-bound state, which is required for maintaining RAB-5 dynamics on phagosomes and serves as a switch for the progression of phagosome maturation.
