A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death
A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death
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DOI：
10.1038/emboj.2011.497
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发表时间：
2012-03-07
期刊：
影响因子：
11.4
通讯作者：
Agostinis, Patrizia
中科院分区：
文献类型：
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作者：
Garg, Abhishek D.;Krysko, Dmitri V.;Agostinis, Patrizia
表面暴露的钙网蛋白（ecto-CRT）和分泌的ATP是免疫原性细胞凋亡的关键损伤相关分子模式（DAMP）。免疫原性细胞凋亡的诱导剂依赖于内质网（ER）为基础的（活性氧（ROS）调节）途径外CRT的诱导，但ATP分泌途径是未知的。我们发现，在产生ROS介导的ER应激的光动力疗法（PDT）后，垂死的癌细胞经历免疫原性凋亡，其特征在于树突状细胞的表型成熟（CD 80（高）、CD 83（高）、CD 86（高）、MHC-II高）和功能刺激（NO高、IL-10（缺乏）、IL-1 β（高））以及保护性抗肿瘤免疫应答的诱导。有趣的是，在PDT后早期，癌细胞在表现出凋亡的生化特征之前显示出外CRT和分泌ATP，通过重叠的PERK协调的途径，其需要功能性分泌途径和磷酸肌醇3-激酶（PI 3 K）介导的质膜/细胞外运输。有趣的是，eIF 2 α磷酸化和半胱天冬酶-8信号传导对于这种外CRT暴露是不稳定的。我们还鉴定了LRP 1/CD 91作为ecto-CRT的表面对接位点，并发现PERK、PI 3 K p110 α和LRP 1的缺失而不是caspase-8的缺失降低了癌细胞的免疫原性。这些结果揭示了一种新的PERK依赖的子程序的早期和同时发射的两个关键DAMP后ROS介导的ER压力。The EMBO Journal（2012）31，1062-1079. doi：10.1038/daj.2011.497; 2012年1月17日在线发布主题分类：信号转导;疾病分子生物学
Surface-exposed calreticulin (ecto-CRT) and secreted ATP are crucial damage-associated molecular patterns (DAMPs) for immunogenic apoptosis. Inducers of immunogenic apoptosis rely on an endoplasmic reticulum (ER)based (reactive oxygen species (ROS)-regulated) pathway for ecto-CRT induction, but the ATP secretion pathway is unknown. We found that after photodynamic therapy (PDT), which generates ROS-mediated ER stress, dying cancer cells undergo immunogenic apoptosis characterized by phenotypic maturation (CD80(high), CD83(high), CD86(high), MHC-IIhigh) and functional stimulation (NOhigh, IL-10(absent), IL-1 beta(high)) of dendritic cells as well as induction of a protective antitumour immune response. Intriguingly, early after PDT the cancer cells displayed ecto-CRT and secreted ATP before exhibiting biochemical signatures of apoptosis, through overlapping PERK-orchestrated pathways that require a functional secretory pathway and phosphoinositide 3-kinase (PI3K)-mediated plasma membrane/extracellular trafficking. Interestingly, eIF2 alpha phosphorylation and caspase-8 signalling are dispensable for this ecto-CRT exposure. We also identified LRP1/CD91 as the surface docking site for ecto-CRT and found that depletion of PERK, PI3K p110 alpha and LRP1 but not caspase-8 reduced the immunogenicity of the cancer cells. These results unravel a novel PERK-dependent subroutine for the early and simultaneous emission of two critical DAMPs following ROS-mediated ER stress. The EMBO Journal (2012) 31, 1062-1079. doi: 10.1038/emboj.2011.497; Published online 17 January 2012 Subject Categories: signal transduction; molecular biology of disease