TET2 promotes UVB-induced cell death by activating RIPK3-MLKL-necroptosis signaling.

Ultraviolet B(UVB) radiation is a leading environmental factor that induces severe photodamage. However, its pathogenic mechanisms remain incompletely understood. Our previous research has found that Ten-eleven translocation 2 (TET2) is significantly upregulated in UVB-irradiated keratinocytes. Here, this study revealed that TET2 was upregulated in photodamaged skin, including specimens from actinic keratosis (AK) patients, UVB-exposed human skin sites, and a photodamaged mouse model. TET2 deficiency in keratinocytes mitigated UVB-induced cell death and photodamage, while TET2 overexpression exacerbated these effects. Furthermore, TET2 prompted keratinocyte death and photodamage mainly by activating the RIPK3-MLKL signaling pathway, with caspase-8 activation contributing secondarily. As for the mechanism, firstly, TET2 increases the expression of RIPK3 and MLKL by promoting their DNA demethylation, and secondly, TET2 directs the binding of PLK3 to RIPK3 and MLKL, thus enhancing the RIPK3-MLKL signaling pathway activation. This work showed that TET2 increases UVB-induced keratinocyte death and photodamage by activating the RIPK3-MLKL signaling pathway. TET2 appears to have a second function that orchestrates host responses to UVB exposure.