TM9SF4 is required for Drosophila cellular immunity via cell adhesion and phagocytosis
TM9SF4 is required for Drosophila cellular immunity via cell adhesion and phagocytosis
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DOI：
10.1242/jcs.030163
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发表时间：
2008-10-15
影响因子：
4
通讯作者：
Fauvarque, Marie-Odile
中科院分区：
文献类型：
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作者：
Bergeret, Evelyne;Perrin, Jackie;Fauvarque, Marie-Odile
非天冬氨酸由一个大的N端胞外域和九个假定的跨膜域组成。这个进化保守的家族包括盘状网柄菌(Phg1A、Phg1B和Phg1C)和黑腹果蝇的3个成员，以及哺乳动物的4个成员(TM9SF1-TM9SF4)，这些成员的功能基本上是未知的。对网柄网柄菌的遗传学研究表明，Phg1a是细胞黏附和吞噬所必需的。我们创造了Phg1A/TM9SF4缺失的突变果蝇，并表明它们对致病的革兰氏阴性细菌敏感，但对革兰氏阳性细菌不敏感。这种敏感性的增加并不是由于Toll或IMD信号受损，而是因为细胞免疫反应有缺陷。TM9SF4缺失的幼虫巨噬细胞吞噬革兰氏阴性杆菌的能力较差，而革兰氏阳性金黄色葡萄球菌吞噬功能正常。突变幼虫的黄蜂卵包裹率也降低了，这一过程需要依赖血细胞与寄生蜂的黏附。细胞免疫缺陷与突变的幼虫血细胞的形态和黏附缺陷有关，血细胞具有异常的肌动蛋白细胞骨架。TM9SF4及其最接近的同源基因TM9SF2都是S2细胞细菌内化所必需的，在S2细胞中它们显示出部分冗余。我们的研究强调了吞噬细胞在具有复杂先天免疫反应的有机体中对宿主防御的贡献，并表明TM9SF4在真核吞噬细胞中具有进化上的保守功能。
Nonaspanins are characterised by a large N-terminal extracellular domain and nine putative transmembrane domains. This evolutionarily conserved family comprises three members in Dictyostelium discoideum (Phg1A, Phg1B and Phg1C) and Drosophila melanogaster, and four in mammals (TM9SF1-TM9SF4), the function of which is essentially unknown. Genetic studies in Dictyostelium demonstrated that Phg1A is required for cell adhesion and phagocytosis. We created Phg1A/TM9SF4-null mutant flies and showed that they were sensitive to pathogenic Gram-negative, but not Gram-positive, bacteria. This increased sensitivity was not due to impaired Toll or Imd signalling, but rather to a defective cellular immune response. TM9SF4-null larval macrophages phagocytosed Gram-negative E. coli inefficiently, although Gram-positive S. aureus were phagocytosed normally. Mutant larvae also had a decreased wasp egg encapsulation rate, a process requiring haemocyte-dependent adhesion to parasitoids. Defective cellular immunity was coupled to morphological and adhesion defects in mutant larval haemocytes, which had an abnormal actin cytoskeleton. TM9SF4, and its closest paralogue TM9SF2, were both required for bacterial internalisation in S2 cells, where they displayed partial redundancy. Our study highlights the contribution of phagocytes to host defence in an organism possessing a complex innate immune response and suggests an evolutionarily conserved function of TM9SF4 in eukaryotic phagocytes.