The ribotoxic stress response drives acute inflammation, cell death, and epidermal thickening in UV-irradiated skin in vivo
Solar UVB light causes damage to the outermost layer of skin. This insult induces rapid local responses, such as dermal inflammation, keratinocyte cell death, and epidermal thickening, all of which have traditionally been associated with DNA damage response signaling. Another stress response that is activated by UVB light is the ribotoxic stress response (RSR), which depends on the ribosome-associated mitogen-activated protein 3 kinases (MAP3K) ZAKα and culminates in p38 and JNK activation. Using ZAK knockout mice, we here show that it is the RSR that is responsible for the early manifestation of UVB-induced skin inflammation and keratinocyte death and subsequent proliferation in vivo. We also show that the RSR controls both p38-mediated pyroptotic and JNK-mediated apoptotic programmed cell death of human keratinocytes in vitro. In sum, our work highlights that skin cells rely on a cytoplasmic and ribosomal stress signal rather than a nuclear and DNA-templated signal for rapid inflammatory responses to UV exposure.
Authors
- Gee Ann Toh (ORCID: https://orcid.org/0000-0002-7417-8376)
- Franklin L. Zhong (ORCID: https://orcid.org/0000-0002-0516-6021)
- Mads Gyrd‐Hansen (ORCID: https://orcid.org/0000-0001-5641-5019)
- Melanie Blasius (ORCID: https://orcid.org/0000-0001-5032-2209)
- Li Fang Koh (ORCID: https://orcid.org/0000-0002-8735-3831)
- Peter Haahr (ORCID: https://orcid.org/0000-0001-9680-2304)
- Thomas Levin Andersen (ORCID: https://orcid.org/0000-0002-6981-7276)
- John Common (ORCID: https://orcid.org/0000-0002-3280-7365)
- Anna Vind (ORCID: https://orcid.org/0000-0001-5074-2713)
- Simon Bekker‐Jensen (ORCID: https://orcid.org/0000-0002-7308-4597)
- Goda Snieckute (ORCID: https://orcid.org/0000-0003-0738-0926)
- Muhammad Jasrie Firdaus (ORCID: https://orcid.org/0000-0003-4843-9605)
- Zhenhua Wu (ORCID: https://orcid.org/0000-0003-4552-883X)
- José Francisco Martı́nez (ORCID: https://orcid.org/0000-0002-3457-2088)
- Malin Jessen (ORCID: https://orcid.org/0009-0007-5929-0064)
- Nina Loeth Maartensson
Institutions
- Agency for Science, Technology and Research (SG)
- University of Copenhagen (DK)
- Nanyang Technological University (SG)
- University of Southern Denmark (DK)
- Copenhagen University Hospital (DK)
- LEO Foundation (DK)
Publication Details
- Journal
- Molecular Cell
- Published
- 2024-11-25
- DOI
- https://doi.org/10.1016/j.molcel.2024.10.044
- Citations
- 33
- Primary Topic
- Skin Protection and Aging
- Type
- article
- Field-Weighted Citation Impact
- 17.64
Funders
- Aarhus Universitet
- Aarhus Universitetshospital
- European Commission
- National Research Foundation
- Agency for Science, Technology and Research
- Danmarks Grundforskningsfond
- Jinan University
- Novo Nordisk
- Odense Universitetshospital
- Ministry of Education, India
- Novo Nordisk Fonden
- LEO Fondet
- Medical Research Council
- National Medical Research Council
- Biomedical Research Council