Ultraviolet radiation induces caspase cleavage and nuclear translocation of heme oxygenase 1 (HO‐1) to activate autophagy in skin keratinocytes
- 9 June 2025
- journal article
- Published by Wiley in The FEBS Journal
- Vol. 292 (19) , 5204-5218
Abstract
The skin is vulnerable to ultraviolet (UV) exposure, and as a repair mechanism, autophagy activation is essential to eliminate UV‐damaged skin cells to maintain tissue homeostasis. As a UV‐induced protein, heme oxygenase‐1 (HO‐1; 32 kDa) is implicated in protecting cells from oxidative stress and plays an important role in disease prevention. However, the mechanism of photoprotection in skin cells has yet to be fully understood. In the current study, we uncovered that UV radiation induces proteolytic cleavage of HO‐1 into a 26 kDa product that accumulates in the cell nucleus. Biochemical analyses show that caspase‐1 (CASP1) directly binds to HO‐1 and cleaves full‐length HO‐1 at the C terminus. It is further unveiled that the 26 kDa HO‐1 product is a stronger activator of autophagy than full‐length HO‐1, as demonstrated by the activation of autophagy‐related genes. Moreover, the 26 kDa HO‐1 cleavage product promotes translocation of the transcription factor basic helix–loop–helix ARNT‐like protein 1 (Bmal1) into the cell nucleus. This translocation appears to be required for the induction of autophagy, as knocking down Bmal1 fails to activate autophagy induced by the 26 kDa HO‐1 cleavage product. We conclude that a proteolytic cascade involving CASP1/HO‐1/Bmal1 acts to modulate autophagy in UV‐irradiated human skin keratinocytes, presumably as a mechanism to mediate UV photoprotection. Our study identified proteolysis as a regulatory event by generating a previously unknown 26 kDa form of HO‐1 to play a distinct role in the activation of autophagy in UV‐exposed epidermal cells.Keywords
Funding Information
- National Key Research and Development Program of China Stem Cell and Translational Research (2023YFC2508200)
- National Natural Science Foundation of China (82373501, 82373461, 82260788)
- Fundamental Research Funds for the Central Universities (2022CDJYGRH‐005, 2022CDJYGRH‐016)
- Deutsche Forschungsgemeinschaft (BA1606/3‐4)
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