P16INK4a upregulation mediated by TBK1 induces retinal ganglion cell senescence in ischemic injury.
P16INK4a upregulation mediated by TBK1 induces retinal ganglion cell senescence in ischemic injury.
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DOI：
10.1038/cddis.2017.169
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发表时间：
2017-04-20
影响因子：
9
通讯作者：
Zhang H
中科院分区：
文献类型：
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作者：
Li LU;Zhao Y;Zhang H
青光眼是世界范围内导致不可逆性失明的主要原因，其特征是进行性视网膜神经节细胞(RGC)死亡。然而，RGC衰老是RGC死亡前的一个阶段，RGC衰老的机制尚不清楚。在这里，我们证明了坦克结合蛋白1(TBK1)在急性眼压升高诱导的视网膜缺血小鼠模型中表达上调。此外，用TBK1抑制剂BX-795预处理可降低p16INK4a(P16)的表达和RGC衰老。Tbk1基因表达上调可增加Akt在Ser473的磷酸化和Bmi1的磷酸化。Akt抑制剂MK-2206可降低p16和Bmi1丝氨酸磷酸化表达。Bmi1 Ser316突变也减弱了TBK1诱导的p16上调。最后，通过shRNA敲除沉默的TBK1减少了p16的表达以及Akt和Bmi1的磷酸化，从而减少了体内RGC的衰老。这些数据表明，急性眼压升高诱导的缺血增加了TBK1的表达，进而通过Akt-Bmi1磷酸化途径增加了p16的表达。因此，本研究阐明了TBK1调节p16表达和RGC衰老的新机制，为减少视网膜缺血和青光眼RGC衰老提供了一种潜在的新的治疗策略。
Glaucoma is a leading cause of irreversible blindness worldwide that is characterized by progressive retinal ganglion cell (RGC) death. However, RGC senescence as a phase before RGC death, and the mechanism of RGC senescence remains unclear. Here, we demonstrate that TANK-binding protein 1 (TBK1) is upregulated in acute IOP elevation-induced ischemic retinas mouse model. Moreover, pre-treatment with the TBK1 inhibitor BX-795 reduced p16INK4a (p16) expression and RGC senescence. Upregulation of TBK1 via plasmid transfection increased Akt phosphorylation at Ser473 and Bmi1 phosphorylation. The Akt inhibitor MK-2206 decreased the expression of p16 and Bmi1 serine phosphorylation. A Bmi1 Ser316 mutation also attenuated TBK1-induced p16 upregulation. Finally, silencing of TBK1 via shRNA knockdown reduced the expression of p16 as well as Akt and Bmi1 phosphorylation, reducing RGC senescence in vivo. These data suggest that acute IOP elevation-induced ischemia increases TBK1 expression, which then increases p16 expression through the Akt- Bmi1 phosphorylation pathway. This study therefore elucidates a novel mechanism whereby TBK1 regulates p16 expression and RGC senescence, suggesting a potential novel treatment strategy for minimizing RGC senescence in retinal ischemia and glaucoma.