IKK alpha mediates UVB-induced cell apoptosis by regulating p53 pathway activation
IKK alpha mediates UVB-induced cell apoptosis by regulating p53 pathway activation
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IKK α 通过调节 p53 通路激活介导 UVB 诱导的细胞凋亡
DOI：
10.1016/j.ecoenv.2021.112892
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发表时间：
2021
影响因子：
6.8
通讯作者：
Song Lun
中科院分区：
文献类型：
--
作者：
Wang Hongli;Zhang Min;Xu Xiuduan;Hou Shaojun;Liu Zhihui;Chen Xuejiao;Zhang Chongchong;Xu Huan;Wu Lin;Liu Kun;Song Lun
紫外线B(UVB)暴露可引起DNA损伤和血管生成相关的光损伤，这些损伤与多种医学问题有关，包括晒伤、光老化和皮肤癌。然而，与UVB诱导的光损伤相关的分子机制仍未完全阐明。在此，我们揭示了IKK复合体的催化亚基之一IKKα在中波紫外线诱导的两种中波紫外线敏感细胞--人角质形成细胞(HACAT)和小鼠胚胎成纤维细胞(MEF)--的凋亡反应中起着关键作用。IKKα的这一功能与NF-κB活性无关，但通过诱导P53的磷酸化和乙酰化以及上调促凋亡的P53靶基因perp的表达来实现。虽然IKKα激酶活性是介导53的翻译后修饰和反式激活以及PERP诱导所必需的，但IKKα并不显示出与P53的直接结合能力。相反，IKKα可以与导致P53磷酸化的蛋白激酶CHK1相互作用，触发CHK1的激活和CHK1/P53复合体的形成。同时，IKKα还可与负责P53乙酰化的乙酰化转移酶p300和CBP相互作用，并在紫外线照射下触发p300/CBP激活和P300/P53或CBP/P53复合体的形成。综上所述，我们发现了一种新的不依赖于NF-κB的IKKα通过调节P53通路的激活来介导UVB诱导的细胞凋亡。靶向IKKα/P53/PERP通路可能有助于预防阳光对皮肤的光损伤。
Exposure to ultraviolet B (UVB) has been demonstrated to induce DNA damage as well as angiogenesis-related photo-damages, which are implicated in a variety of medical problems, including sunburn, photo-aging and skin cancers. However, the molecular mechanism related to UVB-induced photo-injuries remained fully elucidated. Here we revealed that one of the catalytic subunits of the IKK complex, IKKα, played a critical role in mediating UVB-induced apoptotic responses in two kinds of UVB sensitive cells, human keratinocyte (HaCat) and mouse embryonic fibroblasts (MEFs). This function of IKKα was unrelated to NF-κB activity, but was delivered by inducing phosphorylation and acetylation of p53 and upregulating the expression of the pro-apoptotic p53 target gene, PERP. Although IKKα kinase activity was required for mediating post-translational modifications and transactivation of 53 and PERP induction, IKKα did not show direct binding ability toward p53. Instead, IKKα could interact with CHK1, the protein kinase leading to p53 phosphorylation, and trigger CHK1 activation and CHK1/p53 complex formation. At the same time, IKKα could also interact with p300 and CBP, the acetyltransferases responsible for p53 acetylation, and trigger p300/CBP activation and p300/p53 or CBP/p53 complex formation under UVB exposure. Taken together, we have identified a novel NF-κB-independent role of IKKα in mediating UVB-induced apoptosis by regulating p53 pathway activation. Targeting IKKα/p53/PERP pathway might be helpful to prevent skin photo-damages induced by sunlight.