interferon and immune responses
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It is shown that IFN-induced Z-DNA binding protein 1 (ZBP1) stabilizes ultraviolet (UV) B-induced cytosolic Z-DNA derived from oxidized mitochondrial DNA and highlights Z-DNA and ZBP1 as critical mediators for UVB-induced inflammation.
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Photosensitivity is observed in numerous autoimmune diseases and drives poor quality of life and disease flares. Elevated epidermal type I interferon (IFN) production primes for photosensitivity and enhanced inflammation, but the substrates that sustain and amplify this cycle remain undefined. We show that IFN-induced Z-DNA binding protein 1 (ZBP1) stabilizes ultraviolet (UV) B-induced cytosolic Z-DNA derived from oxidized mitochondrial DNA. ZBP1 is up-regulated in the epidermis of adult and pediatric patients with autoimmune photosensitivity. In patient-derived samples, lupus keratinocytes accumulate extensive cytosolic Z-DNA after UVB exposure, and transfection of keratinocytes with Z-DNA results in stronger IFN production through cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) activation compared with the more conventional B-DNA. ZBP1 knockdown abrogates UVB-induced IFN responses, whereas overexpression results in a lupus-like phenotype with spontaneous Z-DNA accumulation and IFN production. Our results highlight Z-DNA and ZBP1 as critical mediators for UVB-induced inflammation and uncover how type I IFNs prime for cutaneous inflammation in photosensitivity.
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@article{Klein2025Epidermal,
title = {Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity},
author = {Benjamin Klein and Mack B. Reynolds and Bin Xu and Mehrnaz Gharaee‐Kermani and Yiqing Gao and Céline C. Berthier and Svenja Henning and Lam C. Tsoi and Shannon Loftus and Kelsey E. McNeely and Christine M. Goudsmit and Amanda Victory and Craig J. Dobry and Grace A. Hile and Feiyang Ma and Jessica L. Turnier and Jóhann E. Guðjónsson and Mary O’Riordan and J. Michelle Kahlenberg},
journal = {Science Immunology},
year = {2025},
doi = {10.1126/sciimmunol.ado1710},
url = {https://doi.org/10.1126/sciimmunol.ado1710}
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