Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity
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.
Authors
- Feiyang Ma (ORCID: https://orcid.org/0000-0002-6260-0787)
- Céline C. Berthier (ORCID: https://orcid.org/0000-0003-3539-1075)
- Bin Xu (ORCID: https://orcid.org/0000-0001-7429-3908)
- Mack B. Reynolds (ORCID: https://orcid.org/0000-0002-8445-3749)
- Craig J. Dobry (ORCID: https://orcid.org/0000-0002-1468-1156)
- Benjamin Klein (ORCID: https://orcid.org/0000-0002-3412-5536)
- Shannon Loftus (ORCID: https://orcid.org/0000-0002-9225-6729)
- Svenja Henning (ORCID: https://orcid.org/0000-0002-7895-6729)
- Kelsey E. McNeely
- Amanda Victory (ORCID: https://orcid.org/0000-0002-4948-5702)
- Jessica L. Turnier (ORCID: https://orcid.org/0000-0002-1127-7879)
- Mehrnaz Gharaee‐Kermani (ORCID: https://orcid.org/0000-0002-2177-2427)
- Lam C. Tsoi (ORCID: https://orcid.org/0000-0003-1627-5722)
- Johann Eli Gudjonsson (ORCID: https://orcid.org/0000-0002-0080-0812)
- Joanne Michelle Kahlenberg (ORCID: https://orcid.org/0000-0002-4006-8945)
- Grace A. Hile (ORCID: https://orcid.org/0000-0002-3629-8633)
- Mary O’Riordan (ORCID: https://orcid.org/0000-0001-6014-4637)
- Christine M. Goudsmit
- Yiqing Gao
Institutions
- University of Michigan (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-03-07
- DOI
- https://doi.org/10.1126/sciimmunol.ado1710
- Citations
- 27
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 21.53
Funders
- American Heart Association
- Barth Syndrome Foundation
- Rheumatology Research Foundation
- University of Michigan
- A. Alfred Taubman Medical Research Institute
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases