Imbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity.
Imbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity.
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不平衡展开的蛋白质反应信号传导有助于1-脱氧胆脂性视网膜毒性。
DOI：
10.1038/s41467-023-39775-w
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发表时间：
2023-07-11
影响因子：
16.6
通讯作者：
Eade, Kevin T.
中科院分区：
文献类型：
--
作者：
Rosarda, Jessica D.;Giles, Sarah;Harkins-Perry, Sarah;Mills, Elizabeth A.;Friedlander, Martin;Wiseman, R. Luke;Eade, Kevin T.
非典型细胞毒性1-脱氧鞘脂（1-dSL）的积累与视网膜疾病（如糖尿病视网膜病变和黄斑毛细血管扩张症2型）有关。然而，1-dSL诱导视网膜细胞毒性的分子机制仍然知之甚少。在这里，我们整合了大量和单核RNA测序，以确定调节人类视网膜类器官中1-dSL毒性的生物学途径。我们的研究结果表明，1-dSL差异激活信号臂的未折叠蛋白反应（UPR）在感光细胞和米勒神经胶质细胞。使用药理学激活剂和抑制剂的组合，我们表明，持续的PERK信号通过综合应激反应（ISR）和缺陷的信号通过保护ATF 6臂的UPR涉及1-DSL诱导的感光细胞毒性。此外，我们证明了ATF 6的药理学激活减轻了1-dSL毒性而不影响PERK/ISR信号传导。总的来说，我们的结果确定了通过针对UPR的不同分支来干预1-dSL相关疾病的新机会。细胞毒性脱氧鞘脂的积累通过未知机制引起视网膜病变。在这里，作者使用视网膜类器官来表明感光细胞毒性是由未折叠蛋白反应信号传导介导的。
The accumulation of atypical, cytotoxic 1-deoxysphingolipids (1-dSLs) has been linked to retinal diseases such as diabetic retinopathy and Macular Telangiectasia Type 2. However, the molecular mechanisms by which 1-dSLs induce toxicity in retinal cells remain poorly understood. Here, we integrate bulk and single-nucleus RNA-sequencing to define biological pathways that modulate 1-dSL toxicity in human retinal organoids. Our results demonstrate that 1-dSLs differentially activate signaling arms of the unfolded protein response (UPR) in photoreceptor cells and Müller glia. Using a combination of pharmacologic activators and inhibitors, we show that sustained PERK signaling through the integrated stress response (ISR) and deficiencies in signaling through the protective ATF6 arm of the UPR are implicated in 1-dSL-induced photoreceptor toxicity. Further, we demonstrate that pharmacologic activation of ATF6 mitigates 1-dSL toxicity without impacting PERK/ISR signaling. Collectively, our results identify new opportunities to intervene in 1-dSL linked diseases through targeting different arms of the UPR. The accumulation of cytotoxic deoxysphingolipids causes retinopathies through unknown mechanisms. Here the authors use retinal organoids to show that photoreceptor toxicity is mediated by unfolded protein response signaling.
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影响因子：
33.6
作者：
Guerriero CJ;Brodsky JL
通讯作者：
Brodsky JL
影响因子：
14.8
作者：
Grandjean JMD;Madhavan A;Cech L;Seguinot BO;Paxman RJ;Smith E;Scampavia L;Powers ET;Cooley CB;Plate L;Spicer TP;Kelly JW;Wiseman RL
通讯作者：
Wiseman RL
鉴定中脑星形胶质细胞衍生的神经营养因子作为视网膜神经节细胞的新型神经保护因子
影响因子：
4.8
作者：
Gao FJ;Wu JH;Li TT;Du SS;Wu Q
通讯作者：
Wu Q
DOI：
10.1038/nrm.2017.107
发表时间：
2018-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Hannun YA;Obeid LM
通讯作者：
Obeid LM
影响因子：
7.7
作者：
Gallagher, Ciara M.;Walter, Peter
通讯作者：
Walter, Peter