2012年6月21日,，我所王曉晨實(shí)驗(yàn)室在《Current Biology》雜志在線發(fā)表題為“C. elegans Secreted Lipid-Binding Protein NRF-5 Mediates PS Appearance on Phagocytes for Cell Corpse Engulfment”的文章。
凋亡細(xì)胞的正常清除可防止其中有害物質(zhì)的外泄而傷害正常細(xì)胞,，從而對(duì)細(xì)胞穩(wěn)態(tài)平衡的調(diào)控起重要作用。凋亡細(xì)胞清除缺陷會(huì)導(dǎo)致炎癥和免疫紊亂,。
該文章以線蟲為模式動(dòng)物,，通過(guò)遺傳篩選克隆獲得了凋亡細(xì)胞吞噬的新調(diào)控因子nrf-5,。NRF-5屬于脂類結(jié)合及轉(zhuǎn)運(yùn)蛋白BPI/LBP/CETP/PLTP家族中的一員。我們的研究發(fā)現(xiàn)NRF-5其是由肌肉細(xì)胞中產(chǎn)生的分泌蛋白,，能特異性的識(shí)別凋亡細(xì)胞表面信號(hào)磷脂酰絲氨酸（phosphatidylserine）,。很有意思的是NRF-5與我們之前發(fā)現(xiàn)的橋聯(lián)分子TTR-52識(shí)別凋亡細(xì)胞的方式是不一樣的。NRF-5識(shí)別凋亡細(xì)胞依賴于CED-7,，一種定位在凋亡細(xì)胞膜和吞噬細(xì)胞膜上ABCA轉(zhuǎn)運(yùn)蛋白,；而TTR-52通過(guò)PS結(jié)合凋亡細(xì)胞。
我們發(fā)現(xiàn)凋亡信號(hào)磷脂酰絲氨酸( PS )不僅可以暴露在凋亡細(xì)胞表面,，在凋亡細(xì)胞周圍緊鄰的吞噬細(xì)胞表面也能檢測(cè)到PS的存在,。這種在吞噬細(xì)胞表面檢測(cè)到的磷脂酰絲氨酸( PS )在nrf-5，ced-7,，ttr-52 的突變體中被特異性的阻斷掉,，而nrf-5，ced-7,，ttr-52 突變體還會(huì)導(dǎo)致PS在凋亡細(xì)胞表面的積累,。通過(guò)體外實(shí)驗(yàn)，我們發(fā)現(xiàn)NRF-5具有脂類轉(zhuǎn)運(yùn)活性,，NRF-5和TTR-52可以相互作用,。我們的研究表明NRF-5與ABC transporter CED-7及橋聯(lián)分子TTR-52共同調(diào)控磷脂酰絲氨酸（PS）從凋亡細(xì)胞表面向鄰近吞噬細(xì)胞表面的轉(zhuǎn)運(yùn)。PS在凋亡細(xì)胞表面的出現(xiàn)介導(dǎo)了凋亡細(xì)胞的識(shí)別和吞噬,，那么PS在吞噬細(xì)胞表面出現(xiàn)又起了什么作用呢,？利用living imaging analysis，我們發(fā)現(xiàn)盡管凋亡細(xì)周圍有多個(gè)具有吞噬能力的吞噬細(xì)胞，絕大多數(shù)凋亡細(xì)胞最終被PS-positive的吞噬細(xì)胞所吞噬,。nrf-5 突變體阻斷了PS在吞噬細(xì)胞表面的出現(xiàn)并顯著延遲了凋亡細(xì)胞的吞噬,，表明具有磷脂酰絲氨酸信號(hào)的吞噬細(xì)胞具有更高的吞噬活性。
生命科學(xué)研究所與協(xié)和醫(yī)科大學(xué)聯(lián)合培養(yǎng)博士生張燕為本文第一作者,，我所博士生王海彬?yàn)榈诙髡?。趙東風(fēng)博士、技術(shù)員林靜和盧明星也參與了此工作,。王曉晨博士為本文通訊作者,。此項(xiàng)研究由科技部863計(jì)劃和北京市科委資助，在北京生命科學(xué)研究所完成,。（生物谷Bioon.com）
doi:10.1016/j.cub.2012.06.004
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. elegans Secreted Lipid-Binding Protein NRF-5 Mediates PS Appearance on Phagocytes for Cell Corpse Engulfment
Yan Zhang, Haibin Wang, Eriko Kage-Nakadai, Shohei Mitani, Xiaochen Wang
Background During programmed cell death, apoptotic cells are rapidly removed by phagocytes. How dying cells are recognized remains poorly understood. Results Here we identify a secreted lipid transfer/LPS-binding family protein, NRF-5, which is required for efficient clearance of cell corpses. We observed that phosphatidylserine (PS), which is externalized to the outer leaflet of plasma membranes in apoptotic cells, is also detected on the surface of engulfing cells. Loss of NRF-5 function completely blocks PS appearance on engulfing cells but causes accumulation of PS on apoptotic cells, a phenotype observed in both ced-7(lf) and ttr-52(lf) mutants. The NRF-5 protein is expressed in and secreted from body wall muscle cells and clusters around apoptotic cells in a CED-7-dependent manner. NRF-5 associates with TTR-52, binds PS, and displays lipid transfer activity in vitro. Conclusion Our data suggest that NRF-5 may act with CED-7 and TTR-52 to mediate PS transfer from apoptotic cells to engulfing cells and thus promotes engulfment by phagocytes.
