ORIGINAL RESEARCH article
Front. Cell Death
Sec. Apoptosis
Volume 4 - 2025 | doi: 10.3389/fceld.2025.1658598
C/EBPβ Deficiency Enhances Keratinocyte Apoptosis after UVB-Induced DNA Damage via Regulation of the Type I IFN and TNF Responses
Provisionally accepted
- North Carolina State University, Raleigh, United States
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The epidermis is routinely subjected to DNA damage induced by ultraviolet B (UVB) solar radiation. In addition to activating canonical DNA damage responses such as cycle cell checkpoints and DNA repair, UVB-induced DNA damage can also activate additional signaling pathways including inflammatory responses. The pathways activated downstream of UVB-induced DNA damage have a critical role in determining cellular survival to UVB radiation. Here we report that loss of CCAAT/enhancer binding protein β (C/EBPβ) in mouse keratinocytes results in enhanced UVB-induced apoptosis through activation of extrinsic apoptosis genes cleaved caspase-8 and truncated BH3 interacting-domain death agonist (tBid). RNAseq and Ingenuity Pathway Analysis of UVB-treated C/EBPβ-/- primary keratinocytes revealed an enrichment of inflammatory signaling pathways, including the type I interferon (IFN-I) pathway as the most enriched pathway. Numerous IFN-I stimulated genes were up-regulated in UVB-treated C/EBPβ-/- keratinocytes, including genes that regulate extrinsic apoptosis. Inhibition of the interferon a/b receptor or the associated kinase Tyk2 greatly reduced cell death in UVB-exposed C/EBPβ deficient keratinocytes, demonstrating the dependence of IFN signaling in C/EBPβ regulated apoptosis. The apoptosis inducing cytokine tumor necrosis factor alpha (TNF-α) was identified as one of the most significant upstream regulators activated in UVB-exposed C/EBPβ-/- keratinocytes compared to UVB exposed wild type control. UVB-exposed C/EBPβ-/- keratinocytes displayed increased expression of TNF-α and the enhanced apoptosis in C/EBPβ-/- keratinocytes was suppressed by a TNF-α neutralizing antibody. Our results indicate that loss of C/EBPβ enhances activation of a non-canonical UVB DNA damage response pathway involving interferon and TNF signaling to induce keratinocyte cell death.
Keywords: Keratinocytes, CCAAT/enhancer-binding protein beta, TNF, UVB, Apopotosis, Inteferon
Received: 04 Jul 2025; Accepted: 20 Aug 2025.
Copyright: © 2025 Tobin, Sharma, Kros, Jima, Gray and Hall. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jonathan Russell Hall, North Carolina State University, Raleigh, United States
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