TET2 amplifies RIPK3/MLKL necroptosis signal by upregulation of PLK3 to promote UVB-induced skin photodamage

Abstract

AbstractThe ultraviolet B (UVB) radiation causes cell death, reactive oxygen species (ROS) accumulation and skin inflammation, which leads to skin photodamage, including skin photoaging, photodermatoses, pigmentary disorders or even skin cancers. However, the mechanism of UVB-induced skin damage remains poorly understood. Here, we find that the expression of ten-eleven translocation 2 (TET2) is upregulated in UVB-irradiated cells and skin tissue. This upregulation leads to increased accumulation of reactive oxygen species (ROS) and cell death, as well as the release of matrix metalloproteinase-1 (MMP-1) and interleukin 6 (IL-6), which accelerates necroinflammation in UVB-irradiated mouse skin. Moreover, the study found that TET2 promotes skin photodamage induced by UVB by upregulating the protein kinase 3 (RIPK3)-mixed lineage kinase domain-like (MLKL) related necroptosis. Mechanistically, TET2 interacts with RIPK3 and MLKL via upregulated polo-like kinase 3 (PLK3), which leads to increased activation of the RIPK3/MLKL/necroptosis signal. These findings have important implications for the prevention and treatment of skin diseases caused by UVB irradiation. By better understanding the mechanisms underlying UVB-induced skin damage, researchers and clinicians may be better equipped to develop strategies for protecting against or treating these conditions.