IKKα mediates UVB-induced cell apoptosis by regulating p53 pathway activation

• Published in: Ecotoxicology and environmental safety 2021-12, Vol.227, p.112892, Article 112892
• Main Authors: Wang, Hongli, Zhang, Min, Xu, Xiuduan, Hou, Shaojun, Liu, Zhihui, Chen, Xuejiao, Zhang, Chongchong, Xu, Huan, Wu, Lin, Liu, Kun, Song, Lun
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Fibroblasts - metabolism; Genes, Tumor Suppressor; Humans; I-kappa B Kinase; IKKα; Keratinocytes; Membrane Proteins; Mice; NF-kappa B - genetics; NF-kappa B - metabolism; P53; PERP; Tumor Suppressor Protein p53 - genetics; Ultraviolet Rays - adverse effects; UVB
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2021.112892

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. •IKKα mediated UVB-induced apoptotic responses in both human keratinocyte (HaCat) and mouse embryonic fibroblasts (MEFs).•The role of IKKα in UVB responses was delivered by NF-κB-unrelated, but p53/PERP-dependent pathway.•IKKα functioned as a coordinator for CHK1 and p300/CBP to mediate the phosphorylation and acetylations of p53.•Manipulation of IKKα/p53/PERP pathway activation may be helpful to prevent UV damage and combat sunlight-induced skin cancer.