GADD34 Ablation Exacerbates Retinal Degeneration in P23H RHO Mice.
GADD34 Ablation Exacerbates Retinal Degeneration in P23H RHO Mice.
复制标题
DOI：
10.3390/ijms232213748
复制
发表时间：
2022-11-09
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
UPR在退化的视网膜中被持续激活，通过p-eIF 2 α导致翻译抑制。最近的研究结果表明，去除生长停滞和DNA损伤诱导蛋白34（GADD 34）（一种蛋白磷酸酶1调节亚基，允许通过p-eIF 2 α升高进行翻译机制操作）不会影响快速退化rd 16小鼠的翻译速率。目前的研究旨在验证P23 H RHO小鼠是否以较慢的速度退化表现出翻译衰减，以及GADD 34消融是否通过进一步抑制视网膜蛋白合成和凋亡细胞死亡来影响视网膜变性的速率。对于本研究，用ERG和组织学分析检查小鼠。使用蛋白质印迹和qRT-PCR分析在未处理和LPS激发的小鼠中进行分子评估。因此，本研究表明，P23 H RHO视网膜表现出翻译衰减。然而，GADD 34消融导致更显著的p-eIF 2a增加，而不影响翻译速率。GADD 34缺陷还导致暗视ERG振幅降低和TUNEL阳性细胞数量增加。分子生物学分析表明，GADD 34缺陷降低了p-STAT 3和IL-6的表达，同时增加了Tnfa的表达。总体而言，数据表明GADD 34发挥多功能作用。在慢性UPR激活下，GADD 34作为反馈参与者，使p-eIF 2a去磷酸化，尽管这种作用似乎并不关键。此外，GADD 34控制细胞因子表达和STAT 3活化。也许这些分子事件在控制视网膜变性的速度方面特别重要。
The UPR is sustainably activated in degenerating retinas, leading to translational inhibition via p-eIF2α. Recent findings have demonstrated that ablation of growth arrest and DNA damage-inducible protein 34 (GADD34), a protein phosphatase 1 regulatory subunit permitting translational machinery operation through p-eIF2α elevation, does not impact the rate of translation in fast-degenerating rd16 mice. The current study aimed to validate whether P23H RHO mice degenerating at a slower pace manifest translational attenuation and whether GADD34 ablation impacts the rate of retinal degeneration via further suppression of retinal protein synthesis and apoptotic cell death. For this study, mice were examined with ERG and histological analyses. The molecular assessment was conducted in the naïve and LPS-challenged mice using Western blot and qRT-PCR analyses. Thus, this study demonstrates that the P23H RHO retinas manifest translational attenuation. However, GADD34 ablation resulted in a more prominent p-eIF2a increase without impacting the translation rate. GADD34 deficiency also led to a reduction in scotopic ERG amplitudes and an increased number of TUNEL-positive cells. Molecular analysis revealed that GADD34 deficiency reduces the expression of p-STAT3 and Il-6 while increasing the expression of Tnfa. Overall, the data indicate that GADD34 plays a multifunctional role. Under chronic UPR activation, GADD34 acts as a feedback player, dephosphorylating p-eIF2a, although this role does not seem to be critical. Additionally, GADD34 controls cytokine expression and STAT3 activation. Perhaps these molecular events are particularly important in controlling the pace of retinal degeneration.
登录
查看更多内容
影响因子：
4.6
作者：
Ito S;Tanaka Y;Oshino R;Aiba K;Thanasegaran S;Nishio N;Isobe K
通讯作者：
Isobe K
DOI：
10.1186/s12964-021-00722-1
发表时间：
2021-04-21
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Seumen CHT;Grimm TM;Hauck CR
通讯作者：
Hauck CR
影响因子：
4.8
作者：
Hollander, MC;Zhan, QM;Fornace, AJ
通讯作者：
Fornace, AJ
DOI：
10.4161/jkst.24353
发表时间：
2013-07-01
期刊：
JAK-STAT
影响因子：
--
作者：
Jonchère B;Bélanger A;Guette C;Barré B;Coqueret O
通讯作者：
Coqueret O
影响因子：
9
作者：
Saltykova IV;Elahi A;Pitale PM;Gorbatyuk OS;Athar M;Gorbatyuk MS
通讯作者：
Gorbatyuk MS