PAT-2/ α Integrin定義吞噬死細胞的一條新遺傳路徑

Abstract

Integrins 是參與細胞黏合、細胞遷移、細胞週期、細胞分化與細胞凋亡等等細胞活動的由異分子組成的細胞表面受器。Integrins 在細胞吞噬過程中的功能已在細胞實驗中發現，但仍缺乏in vivo的證據。PAT-2是線蟲兩種α次分子中的一種，前人的研究發現PAT-2參與線蟲體壁肌肉肌節的形成，pat-2的功能喪失會造成胚胎體軸的延長停留在2-fold時期。我們發現在pat-2 loss-of-function (lf)的胚胎中，細胞屍體的數量比起野生型胚胎有顯著上升的情形。利用time-lapse microscopic recording進行分析，我們發現細胞屍體的數量上升是由於移除細胞屍體的過程受到影響所導致。目前已知在線蟲中有兩條細胞屍體的吞噬路徑，分別由ced-1、 ced-6、ced-7 與ced-2、ced-5、ced-12 組成。我們的研究發現pat-2並不作用在這兩條路徑中，而是與參與肌肉肌節的形成的基因成員一起作用以促進細胞屍體的吞噬。PAT-2在肌肉細胞專一性的表現能消除 pat-2(lf)的胚胎中細胞屍體數量上升的情形，而PAT-2在表皮細胞中的功能也在我們的研究中發現。以上結果顯示，PAT-2 integrin定義了一條新的細胞吞噬路徑，此路徑在肌肉細胞中扮演重要功能，並可能也作用在其他細胞種類。

Integrins are heterodimeric transmembrane receptors that function in cell adhesion, migration, cell cycle progression, differentiation and apoptosis. Its role in the phagocytosis of apoptotic cells has been shown in cultured mammalian cells but has not yet been characterized in vivo. There are two α subunits, PAT-2 and INA-1, and a sole β subunit, PAT-3, in C. elegans. PAT-2 is known to be essential for sarcomere assembly and pat-2 mutants arrested at the 2-fold stage when active muscle movements start. We found that in pat-2 loss-of -function embryos the number of cell corpses significantly increased when compared with that of wild type. A time-lapse microscopic recording showed that the increase of cell corpse number in the pat-2(st567) embryos was due to the failure of cell-corpse removal. C. elegans cell-corpse engulfment was previously shown to be mediated by two partially redundant pathways, ced-1, ced-6, ced-7 in one and ced-2, ced-5 and ced-12 in the other. Clustering of PAT-2 around cell corpses was not affected by ced-1 or ced-5 mutation. In addition, the pat-2 mutation further enhanced the single mutants or double mutants between the two pathways, suggesting that pat-2 may function in a third engulfment pathway. Like pat-2, other genes involved in the body wall muscle assembly also function of cell-corpse engulfment, likely in the same pathway with pat-2. Muscle-specific expression of pat-2 rescued the corpse-engulf-defect of pat-2 embryos. This result indicates that muscle cells, at least primarily, act as engulfing cells in the PAT-2-mediated engulfment process. We conclude that PAT-2 integrin defines a novel engulfment pathway in muscle cells.