Necrotic Cells Actively Attract Phagocytes through the Collaborative Action of Two Distinct PS-Exposure Mechanisms.
Necrotic Cells Actively Attract Phagocytes through the Collaborative Action of Two Distinct PS-Exposure Mechanisms.
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DOI：
10.1371/journal.pgen.1005285
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发表时间：
2015-06
期刊：
影响因子：
4.5
通讯作者：
Zhou Z
中科院分区：
文献类型：
--
作者：
Li Z;Venegas V;Nagaoka Y;Morino E;Raghavan P;Audhya A;Nakanishi Y;Zhou Z
坏死是一种与发病机制和遗传程序密切相关的细胞死亡，与凋亡在形态和机制上都有很大区别。像凋亡细胞一样，坏死细胞被迅速从动物体内清除，以防止有害的炎症和自身免疫反应。在线虫秀丽隐杆线虫中，某些离子通道亚基的功能获得性突变导致6个触觉神经元的兴奋性毒性坏死及其随后的吞噬细胞内的吞噬和降解。吞噬细胞如何识别坏死细胞尚不清楚。磷脂酰丝氨酸（PS）是一种重要的吞噬细胞表面信号，吸引吞噬细胞。在这里，我们观察到坏死的触觉神经元表面的PS暴露。此外，吞噬受体CED-1聚集在坏死细胞周围并促进其吞噬。CED-1的胞外结构域在体外与PS缔合。我们进一步确定了CED-7（ATP结合盒（ABC）转运蛋白家族成员）在促进PS暴露中的坏死细胞特异性功能。除了CED-7、anoctamin homolog-1（ANOH-1）外，C.哺乳动物Ca 2+依赖性磷脂乱序酶TMEM 16 F的elegans同源物，在促进坏死细胞上的PS暴露中起独立作用。CED-7和ANOH-1的组合活性确保了PS有效地暴露于坏死细胞上以吸引它们的吞噬细胞。此外，CED-8、C.哺乳动物Xk相关蛋白8的秀丽线虫同源物也有助于在第一幼虫阶段去除坏死细胞。我们的工作表明，被不同机制（坏死或凋亡）杀死的细胞暴露出一个共同的“吃我”信号来吸引它们的吞噬受体;此外，与以前认为的不同，坏死细胞通过至少两种不同的分子机制主动在其外表面呈现PS，而不是被动地泄漏PS。坏死是通常由细胞损伤引起的一种细胞死亡，并且与包括神经元变性、中风和癌症在内的人类疾病有关。坏死细胞在被吞噬细胞吞噬和降解之前经历明显的形态学变化，包括肿胀。从动物体内清除坏死细胞对于伤口愈合和防止有害的炎症和自身免疫反应是重要的。然而，坏死细胞被去除的机制仍然难以捉摸。我们研究了线虫C.优美的人们普遍认为，坏死细胞的质膜破裂，从而可以通过吞噬细胞表面的特定跨膜受体检测到磷脂酰丝氨酸（PS），即所谓的“吃我”信号分子。与这种信念相反，我们发现，坏死的神经元积极提出PS的外表面通过两个平行的分子机制，其中之一是共享的细胞凋亡，“细胞自杀”的事件，而另一个是唯一的坏死细胞。Ca 2+内流，一个关键因素，触发坏死，涉及激活一个独特的PS-scramblase。我们的研究结果揭示了新的坏死细胞特异性“吃我”信号暴露机制，并表明通过不同机制（坏死和凋亡）死亡的细胞利用共同和独特的机制来吸引吞噬细胞。进一步证明了C.线虫是研究坏死细胞命运的有效模型系统。
Necrosis, a kind of cell death closely associated with pathogenesis and genetic programs, is distinct from apoptosis in both morphology and mechanism. Like apoptotic cells, necrotic cells are swiftly removed from animal bodies to prevent harmful inflammatory and autoimmune responses. In the nematode Caenorhabditis elegans, gain-of-function mutations in certain ion channel subunits result in the excitotoxic necrosis of six touch neurons and their subsequent engulfment and degradation inside engulfing cells. How necrotic cells are recognized by engulfing cells is unclear. Phosphatidylserine (PS) is an important apoptotic-cell surface signal that attracts engulfing cells. Here we observed PS exposure on the surface of necrotic touch neurons. In addition, the phagocytic receptor CED-1 clusters around necrotic cells and promotes their engulfment. The extracellular domain of CED-1 associates with PS in vitro. We further identified a necrotic cell-specific function of CED-7, a member of the ATP-binding cassette (ABC) transporter family, in promoting PS exposure. In addition to CED-7, anoctamin homolog-1 (ANOH-1), the C. elegans homolog of the mammalian Ca2+-dependent phospholipid scramblase TMEM16F, plays an independent role in promoting PS exposure on necrotic cells. The combined activities from CED-7 and ANOH-1 ensure efficient exposure of PS on necrotic cells to attract their phagocytes. In addition, CED-8, the C. elegans homolog of mammalian Xk-related protein 8 also makes a contribution to necrotic cell-removal at the first larval stage. Our work indicates that cells killed by different mechanisms (necrosis or apoptosis) expose a common “eat me” signal to attract their phagocytic receptor(s); furthermore, unlike what was previously believed, necrotic cells actively present PS on their outer surfaces through at least two distinct molecular mechanisms rather than leaking out PS passively. Necrosis is a type of cell death often caused by cell injury and is linked to human diseases including neuron degeneration, stroke, and cancer. Necrotic cells undergo distinct morphological changes, including swelling, before being engulfed and degraded by engulfing cells. The clearance of necrotic cells from animal bodies is important for wound healing and for preventing harmful inflammatory and autoimmune responses. However, the mechanisms by which necrotic cells are removed remain elusive. We study the recognition of necrotic neurons in the nematode C. elegans. There is a common belief that the plasma membrane of necrotic cells are ruptured, allowing the detection of phosphatidylserine (PS), a so-called “eat me” signal molecule, by specific transmembrane receptors on the surface of engulfing cells. Contrary to this belief, we found that necrotic neurons actively present PS to their outer surface through two parallel molecular mechanisms, one of which is shared by cells undergoing apoptosis, a “cell suicide” event, whereas the other is unique to necrotic cells. Ca2+-influx, a key factor that triggers necrosis, is implicated in activating a unique PS-scramblase. Our findings reveal novel necrotic cell-specific “eat me” signal-exposure mechanisms and indicate that cells that die through different mechanisms (necrosis and apoptosis) utilize both common and unique mechanisms to attract engulfing cells. They further demonstrate that C. elegans is an effective model system for studying the fate of necrotic cells.
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影响因子：
8
作者：
Challa, Sreerupa;Chan, Francis Ka-Ming
通讯作者：
Chan, Francis Ka-Ming
影响因子：
21.3
作者：
Chung, SB;Gumienny, TL;Driscoll, M
通讯作者：
Driscoll, M
影响因子：
9.2
作者：
Chen, Bojun;Liu, Qiang;Wang, Zhao-Wen
通讯作者：
Wang, Zhao-Wen
影响因子：
2.7
作者：
CHALFIE, M;SULSTON, J
通讯作者：
SULSTON, J
DOI：
10.1083/jcb.201004096
发表时间：
2010-06-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Elliott MR;Ravichandran KS
通讯作者：
Ravichandran KS