Tribbles homolog 3-mediated targeting the AKT/mTOR axis in mice with retinal degeneration.
Tribbles homolog 3-mediated targeting the AKT/mTOR axis in mice with retinal degeneration.
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DOI：
10.1038/s41419-021-03944-w
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发表时间：
2021-07-02
影响因子：
9
通讯作者：
Gorbatyuk MS
中科院分区：
文献类型：
--
作者：
Saltykova IV;Elahi A;Pitale PM;Gorbatyuk OS;Athar M;Gorbatyuk MS
各种视网膜退行性疾病表现为AKT/mTOR轴的改变。尽管如此，关于mTOR在退行性视网膜中的治疗靶点尚未达成共识。因此，我们研究了AKT/mTOR信号在rd16视网膜中的作用，我们通过基因消融假激酶TRB3来恢复AKT/mTOR轴，已知假激酶TRB3抑制AKT和mTOR的磷酸化。首先，我们发现TRB3消融导致退行性视网膜的光感受器功能得以保留。然后，我们了解到参与光感受器稳态的mTOR下游细胞通路在rd16 TRB3−/−视网膜中也被重编程。因此，在这些小鼠中，随着翻译速率的恢复，失活的翻译抑制因子p-4E-BP1的水平显著升高。此外，在P15时p-mTOR下降的rd16小鼠中，我们发现Beclin-1和ATG5自噬基因的表达升高。因此，通过测量LC3转化和p62积累的增加，这些小鼠显示出受损的自噬通量。此外，RFP-EGFP-LC3转基因在rd16视网膜中的表达导致光感受器中的红点数量减少，这表明晚期自噬空泡受损。相比之下，这些小鼠的TRIB3消融导致自噬通量增加。翻译速率的恢复和自噬体形成的增加伴随着总Ub和视紫红质蛋白水平的增加以及E3连接酶Parkin1的升高。我们认为TRB3可能延缓视网膜变性，是治疗各种视网膜退行性疾病的有希望的治疗靶点。
Various retinal degenerative disorders manifest in alterations of the AKT/mTOR axis. Despite this, consensus on the therapeutic targeting of mTOR in degenerating retinas has not yet been achieved. Therefore, we investigated the role of AKT/mTOR signaling in rd16 retinas, in which we restored the AKT/mTOR axis by genetic ablation of pseudokinase TRB3, known to inhibit phosphorylation of AKT and mTOR. First, we found that TRB3 ablation resulted in preservation of photoreceptor function in degenerating retinas. Then, we learned that the mTOR downstream cellular pathways involved in the homeostasis of photoreceptors were also reprogrammed in rd16 TRB3−/− retinas. Thus, the level of inactivated translational repressor p-4E-BP1 was significantly increased in these mice along with the restoration of translational rate. Moreover, in rd16 mice manifesting decline in p-mTOR at P15, we found elevated expression of Beclin-1 and ATG5 autophagy genes. Thus, these mice showed impaired autophagy flux measured as an increase in LC3 conversion and p62 accumulation. In addition, the RFP-EGFP-LC3 transgene expression in rd16 retinas resulted in statistically fewer numbers of red puncta in photoreceptors, suggesting impaired late autophagic vacuoles. In contrast, TRIB3 ablation in these mice resulted in improved autophagy flux. The restoration of translation rate and the boost in autophagosome formation occurred concomitantly with an increase in total Ub and rhodopsin protein levels and the elevation of E3 ligase Parkin1. We propose that TRB3 may retard retinal degeneration and be a promising therapeutic target to treat various retinal degenerative disorders.
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影响因子：
17.8
作者：
Gorbatyuk MS;Starr CR;Gorbatyuk OS
通讯作者：
Gorbatyuk OS
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作者：
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