UVA, UVB and UVC Induce Differential Response Signaling Pathways Converged on the eIF2α Phosphorylation

It is clear that solar UV irradiation is a crucial environmental factor resulting in skin diseases partially through activation of cell signaling toward altered gene expression and reprogrammed protein translation. Such a key translational control mechanism is executed by the eukaryotic initiation factor 2 alpha subunit (eIF2 alpha) and the downstream events provoked by phosphorylation of eIF2 alpha at Ser(51) are clearly understood, but the upstream signaling mechanisms on the eIF2 alpha-Ser(51) phosphorylation responses to different types of UV irradiations, namely UVA, UVB and UVC, are still not well elucidated. Herein, our evidence reveals that UVA, UVB and UVC all induce a dose- and time-dependent phosphorylation of eIF2 alpha-Ser(51) through distinct signaling mechanisms. UVA-induced eIF2 alpha phosphorylation occurs through MAPKs, including ERKs, JNKs and p38 kinase, and phosphatidylinositol (PI)-3 kinase. By contrast, UVB-induced eIF2 alpha phosphorylation is through JNKs and p38 kinase, but not ERKs or PI-3 kinase, whereas UVC-stimulated response to eIF2 alpha phosphorylation is via JNKs alone. Furthermore, we have revealed that ATM is involved in induction of the intracellular responses to UVA and UVB, rather than UVC. These findings demonstrate that wavelength-specific UV irradiations activate differential response signaling pathways converged on the eIF2 alpha phosphorylation. Importantly, we also show evidence that a direct eIF2 alpha kinase PKR is activated though phosphorylation by either RSK1 or MSK1, two downstream kinases of MAPKs/PI-3 kinase-mediated signaling pathways.