ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load.
ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load.
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DOI：
10.1038/s41467-020-19352-1
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发表时间：
2020-11-05
影响因子：
16.6
通讯作者：
Zode GS
中科院分区：
文献类型：
--
作者：
Kasetti RB;Patel PD;Maddineni P;Patil S;Kiehlbauch C;Millar JC;Searby CC;Raghunathan V;Sheffield VC;Zode GS
青光眼小梁网（TM）损伤和眼压（IOP）升高的潜在病理机制尚不清楚。本文报道慢性内质网（ER）应激诱导的ATF4-CHOP-GADD34通路在人和小鼠青光眼TM中被激活。ATF4在TM中的表达促进异常蛋白合成和ER客户端蛋白负荷，导致TM功能障碍和细胞死亡。这些事件导致IOP升高和青光眼神经变性。ATF4与CHOP相互作用，这种相互作用对IOP升高至关重要。值得注意的是，ATF4-CHOP-GADD34通路的基因缺失或药理抑制可通过减少TM细胞的蛋白质合成和内质网客户端蛋白负荷来阻止TM细胞死亡并挽救小鼠青光眼模型。重要的是，青光眼TM细胞在ATF4-CHOP-GADD34通路的诱导下，蛋白合成显著增加。这些研究提示了ATF4-CHOP-GADD34通路在青光眼中的病理作用，并为靶向该通路治疗青光眼提供了可能。青光眼是导致不可逆失明的主要原因，影响着全球超过7000万人。在这里，作者表明，抑制慢性内质网应激诱导的ATF4-CHOP-GADD34信号通路可以挽救青光眼小鼠模型的病理，从而提出了一种可能的治疗策略。
The underlying pathological mechanisms of glaucomatous trabecular meshwork (TM) damage and elevation of intraocular pressure (IOP) are poorly understood. Here, we report that the chronic endoplasmic reticulum (ER) stress-induced ATF4-CHOP-GADD34 pathway is activated in TM of human and mouse glaucoma. Expression of ATF4 in TM promotes aberrant protein synthesis and ER client protein load, leading to TM dysfunction and cell death. These events lead to IOP elevation and glaucomatous neurodegeneration. ATF4 interacts with CHOP and this interaction is essential for IOP elevation. Notably, genetic depletion or pharmacological inhibition of ATF4-CHOP-GADD34 pathway prevents TM cell death and rescues mouse models of glaucoma by reducing protein synthesis and ER client protein load in TM cells. Importantly, glaucomatous TM cells exhibit significantly increased protein synthesis along with induction of ATF4-CHOP-GADD34 pathway. These studies indicate a pathological role of ATF4-CHOP-GADD34 pathway in glaucoma and provide a possible treatment for glaucoma by targeting this pathway. Glaucoma is the leading cause of irreversible blindness affecting over 70 million people worldwide. Here, the authors show that inhibition of chronic ER stress-induced ATF4-CHOP-GADD34 signaling pathway rescues pathology in mouse models of glaucoma, thus suggesting a possible treatment strategy.
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影响因子：
21.3
作者：
通讯作者：
--
影响因子：
4.4
作者：
Kasetti RB;Phan TN;Millar JC;Zode GS
通讯作者：
Zode GS
DOI：
10.1073/pnas.1706193114
发表时间：
2017-10-17
影响因子：
11.1
作者：
Jain, Ankur;Zode, Gulab;Sheffield, Val C.
通讯作者：
Sheffield, Val C.
影响因子：
4.4
作者：
Chou, Tsung-Han;Bohorquez, Jorge;Porciatti, Vittorio
通讯作者：
Porciatti, Vittorio
影响因子：
6.2
作者：
Beckel, Jonathan M.;Argall, Arthur J.;Lim, Jason C.;Xia, Jingsheng;Lu, Wennan;Coffey, Erin E.;Macarak, Edward J.;Shahidullah, Mohammed;Delamere, Nicholas A.;Zode, Gulab S.;Sheffield, Val C.;Shestopalov, Valery I.;Laties, Alan M.;Mitchell, Claire H.
通讯作者：
Mitchell, Claire H.