Julia Li Zhong

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.

Mycobacterium abscessus is one of the common clinical non-tuberculous mycobacteria (NTM) that can cause severe skin infection. 5-Aminolevulinic acid photodynamic therapy (ALA_PDT) is an emerging effective antimicrobial treatment. To explore whether ALA_PDT can be used to treat M. abscessus infections, we conducted a series of experiments in vitro. We found that ALA_PDT can kill M. abscesses. Mechanistically, we found that ALA_PDT promoted ferroptosis-like death of M. abscesses, and the ROS scavenger N-Acetyl-L-cysteine (NAC) and ferroptosis inhibitor Ferrostatin-1 (Fer-1) can mitigate the ALA_PDT-mediated sterilization. Furthermore, ALA_PDT significantly up-regulated the transcription of heme oxygenase MAB_4773, increased the intracellular Fe²⁺ concentration and altered the transcription of M. abscessus iron metabolism genes. ALA_PDT disrupted the integrity of the cell membrane and enhanced the permeability of the cell membrane, as evidenced by the boosted sterilization effect of antibiotics. In summary, ALA_PDT can kill M. abscesses via promoting the ferroptosis-like death and antibiotic sterilization through oxidative stress by changing iron metabolism. The study provided new mechanistic insights into the clinical efficacy of ALA_PDT against M. abscessus.