Gasdermin E mediates photoreceptor damage by all-trans-retinal in the mouse retina.
Gasdermin E mediates photoreceptor damage by all-trans-retinal in the mouse retina.
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Gasdermin E 通过全反式视网膜介导小鼠视网膜光感受器损伤
DOI：
10.1016/j.jbc.2021.101553
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Cai B;Liao C;He D;Chen J;Han J;Lu J;Qin K;Liang W;Wu X;Liu Z;Wu Y
全反式视网膜（atRAL）清除率的破坏与干性年龄相关性黄斑变性（AMD）和常染色体隐性遗传斯塔加特病（STGD1）中的感光细胞死亡密切相关，但其机制仍然难以捉摸。在这里，我们证明，激活gasdermin E (GSDME)而不是gasdermin D可以通过线粒体介导的caspase-3依赖性信号通路激活细胞焦亡并加剧细胞凋亡，从而促进atRAL诱导的光感受器损伤。 c-Jun N 末端激酶的激活被认为是 atRAL 负载感光细胞中线粒体膜破裂的主要原因之一，导致细胞色素 c 从线粒体释放到胞质溶胶，在胞质溶胶中刺激裂解 GSDME 所需的 caspase-3 激活。 GSDME N 端片段在线粒体中的聚集表明，在 atRAL 暴露后，GSDME 可能会穿透感光细胞中的线粒体膜。 ABC（A 亚科，成员 4）和全反式视黄醇脱氢酶 8 是负责清除视网膜中 atRAL 的两个关键蛋白。 Abca4−/−Rdh8−/− 小鼠在光照下表现出严重的 atRAL 清除缺陷，可作为干性 AMD 和 STGD1 的急性模型。我们发现 GSDME 的 N 端片段明显位于暴露于光的 Abca4−/−Rdh8−/− 小鼠的光感受器外核层中。值得注意的是，Abca4−/−Rdh8−/−Gsdme−/− 小鼠暴露于光后，光感受器的变性和 caspase-3 激活显着减轻。这项研究的结果表明，GSDME 是 atRAL 超载引起的光感受器焦亡和细胞凋亡的常见致病因素，表明抑制 GSDME 可能代表干性 AMD 和 STGD1 光感受器萎缩的潜在治疗方法。
The breakdown of all-trans-retinal (atRAL) clearance is closely associated with photoreceptor cell death in dry age-related macular degeneration (AMD) and autosomal recessive Stargardt's disease (STGD1), but its mechanisms remain elusive. Here, we demonstrate that activation of gasdermin E (GSDME) but not gasdermin D promotes atRAL-induced photoreceptor damage by activating pyroptosis and aggravating apoptosis through a mitochondria-mediated caspase-3-dependent signaling pathway. Activation of c-Jun N-terminal kinase was identified as one of the major causes of mitochondrial membrane rupture in atRAL-loaded photoreceptor cells, resulting in the release of cytochrome c from mitochondria to the cytosol, where it stimulated caspase-3 activation required for cleavage of GSDME. Aggregation of the N-terminal fragment of GSDME in the mitochondria revealed that GSDME was likely to penetrate mitochondrial membranes in photoreceptor cells after atRAL exposure. ABC (subfamily A, member 4) and all-trans-retinol dehydrogenase 8 are two key proteins responsible for clearing atRAL in the retina. Abca4−/−Rdh8−/− mice exhibit serious defects in atRAL clearance upon light exposure and serve as an acute model for dry AMD and STGD1. We found that N-terminal fragment of GSDME was distinctly localized in the photoreceptor outer nuclear layer of light-exposed Abca4−/−Rdh8−/− mice. Of note, degeneration and caspase-3 activation in photoreceptors were significantly alleviated in Abca4−/−Rdh8−/−Gsdme−/− mice after exposure to light. The results of this study indicate that GSDME is a common causative factor of photoreceptor pyroptosis and apoptosis arising from atRAL overload, suggesting that repressing GSDME may represent a potential treatment of photoreceptor atrophy in dry AMD and STGD1.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
视网膜类似（视觉）周期的化学。
影响因子：
62.1
作者：
Kiser, Philip D.;Golczak, Marcin;Palczewski, Krzysztof
通讯作者：
Palczewski, Krzysztof
影响因子：
64.8
作者：
Shi, Jianjin;Zhao, Yue;Shao, Feng
通讯作者：
Shao, Feng
铁死亡导致全视网膜间隙缺陷小鼠的光感受器变性
DOI：
10.1074/jbc.ra120.015779
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Chen C;Chen J;Wang Y;Liu Z;Wu Y
通讯作者：
Wu Y
影响因子：
4.8
作者：
Maeda, Akiko;Maeda, Tadao;Palczewski, Krzysztof
通讯作者：
Palczewski, Krzysztof