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Identification of two evolutionarily conserved genes regulating processing of engulfed apoptotic cells

机译：鉴定两个调控吞噬细胞凋亡过程的进化保守基因

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摘要

Engulfment of apoptotic cells occurs throughout life in multicel-lular organisms. Impaired apoptotic cell clearance (due to defective recognition, internalization or degradation) results in autoimmune disease. One fundamental challenge in understanding how defects in corpse removal translate into diseased states is the identification of critical components orchestrating the different stages of engulfment. Here we use genetic, cell biological and molecular studies in Caenorhabditis elegans and mammalian cells to identify SAND-1 and its partner CCZ-1 as new factors in corpse removal. In worms deficient in either sand-1 or ccz-1, apoptotic cells are internalized and the phagosomes recruit the small GTPase RAB-5 but fail to progress to the subsequent RAB-7(+) stage. The mammalian orthologues of SAND-1, namely Monla and Monlb, were similarly required for phagosome maturation. Mechanistically, Monl interacts with GTP-bound Rab5, identifying Monl as a previously unrecognized Rab5 effector. Moreover, a Monl-Ccz1 complex (but not either protein alone) could bind Rab7 and could also influence Rab7 activation, suggesting Monl-Ccz1 as an important link in progression from the Rab5-positive stage to the Rab7-positive stage of phagosome maturation. Taken together, these data identify SAND-1 (Monl) and CCZ-1 (Ccz1) as critical and evolutionarily conserved components regulating the processing of ingested apoptotic cell corpses.
机译：凋亡细胞在整个生命中都发生在多层生物中。凋亡细胞清除能力受损（由于识别，内在化或降解缺陷）导致自身免疫性疾病。理解去除尸体中的缺陷如何转化为疾病状态的一个基本挑战是确定组织不同吞噬阶段的关键成分。在这里，我们利用秀丽隐杆线虫和哺乳动物细胞的遗传，细胞生物学和分子研究，确定SAND-1及其伴侣CCZ-1是去除尸体的新因素。在缺乏sand-1或ccz-1的蠕虫中，凋亡细胞会被内化，吞噬体会募集小的GTPase RAB-5，但无法进入随后的RAB-7（+）阶段。 SAND-1的哺乳动物直向同源物，即Monla和Monlb，对于吞噬体的成熟也同样需要。从机理上讲，Monl与GTP结合的Rab5相互作用，从而确定Monl是以前无法识别的Rab5效应子。此外，Monl-Ccz1复合体（但不能单独结合两种蛋白质）可以结合Rab7，还可以影响Rab7活化，这表明Monl-Ccz1是吞噬体成熟过程中从Rab5阳性阶段发展到Rab7阳性阶段的重要环节。综上所述，这些数据将SAND-1（Mon1）和CCZ-1（Ccz1）识别为调节摄入的凋亡细胞尸体加工的关键且进化上保守的成分。

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  • 来源
    《Nature》 |2010年第7289期|778-782|共5页
  • 作者

    Jason M. Kinchen; Kodi S. Ravichandran;

  • 作者单位

    Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22908, USA Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908, USA;

    Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22908, USA Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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