CED-1, CED-7, and TTR-52 regulate surface phosphatidylserine expression on apoptotic and phagocytic cells.
CED-1, CED-7, and TTR-52 regulate surface phosphatidylserine expression on apoptotic and phagocytic cells.
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DOI：
10.1016/j.cub.2012.05.052
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发表时间：
2012-07-24
期刊：
影响因子：
9.2
通讯作者：
Xue, Ding
中科院分区：
文献类型：
--
作者：
Mapes, James;Chen, Yu-Zen;Kim, Anna;Mitani, Shohei;Kang, Byung-Ho;Xue, Ding
磷脂酰丝氨酸（PS）通常局限于质膜（PM）的胞质小叶，在细胞凋亡期间外化到外质小叶（exPS），在那里它充当吞噬细胞的“吃我”信号。此外，一些活细胞如巨噬细胞也表达exPS。分泌型膜联蛋白V（sAnxV：：GFP）PS传感器揭示exPS在C. elegans胚胎和老年人或未吞噬凋亡细胞减少。exPS表达的这种减少会因ATP结合盒（ABC）转运蛋白CED-7或分泌型PS结合蛋白TTR-52的丢失而被阻止。吞噬细胞还表达exPS，其依赖于CED-7、TTR-52和TTR-52相互作用的吞噬细胞受体CED-1的活性。有趣的是，分泌的Lactadherin PS传感器（sGFP：：LactC 1C 2）标记凋亡细胞但不标记吞噬细胞，阻止sAnxV：：GFP标记吞噬细胞，并损害吞噬作用。表达sAnxV：：GFP或sGFP：：LactC 1C 2的胚胎的免疫电子显微照片揭示了在凋亡细胞和相邻细胞之间存在细胞外含PS囊泡，其分别在ced-7和ttr-52突变体中不存在或大大减少，表明CED-7和TTR-52促进细胞外PS囊泡的产生。丢失的达特-1基因，保持PS不对称的PM，恢复吞噬细胞exPS的表达ced-1，ced-7，和ttr-52突变体和部分挽救他们的吞噬缺陷。CED-7和TTR-52可能通过产生细胞外PS囊泡促进PS从凋亡细胞中流出，这导致吞噬细胞通过TTR-52和CED-1表达exPS以促进细胞尸体清除。
Phosphatidylserine (PS) normally confined to the cytoplasmic leaflet of plasma membrane (PM) is externalized to the exoplasmic leaflet (exPS) during apoptosis where it serves as an “eat-me” signal to phagocytes. In addition, some living cells such as macrophages also express exPS. A secreted Annexin V (sAnxV::GFP) PS sensor reveals that exPS appears early on apoptotic cells in C. elegans embryos and decreases in older or unengulfed apoptotic cells. This decrease in exPS expression is blocked by loss of CED-7, an ATP binding cassette (ABC) transporter, or TTR-52, a secreted PS binding protein. Phagocytic cells also express exPS, which is dependent on the activity of CED-7, TTR-52, and TTR-52-interacting phagocyte receptor CED-1. Interestingly, a secreted Lactadherin PS sensor (sGFP::LactC1C2) labels apoptotic cells but not phagocytes, prevents sAnxV::GFP from labeling phagocytes, and compromises phagocytosis. Immunoelectron micrographs of embryos expressing sAnxV::GFP or sGFP::LactC1C2 reveal the presence of extracellular PS-containing vesicles between the apoptotic cell and neighboring cells, which are absent or greatly reduced in the ced-7 and ttr-52 mutants, respectively, indicating that CED-7 and TTR-52 promote the generation of extracellular PS vesicles. Loss of the tat-1 gene, which maintains PS asymmetry in the PM, restores phagocyte exPS expression in ced-1, ced-7, and ttr-52 mutants and partially rescues their engulfment defects. CED-7 and TTR-52 may promote the efflux of PS from apoptotic cells through the generation of extracellular PS vesicles, which lead to exPS expression on phagocytes via TTR-52 and CED-1 to facilitate cell corpse clearance.
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