PKCzeta protects against UV-C-induced apoptosis by inhibiting acid sphingomyelinase-dependent ceramide production
Résumé
In a recent study, we described that UV-C irradiation resulted in redox-dependent activation and relocalization of acid sphingomyelinase (A-SMase) to the external surface of raft membrane microdomains, hydrolysis of sphingomyelin (SM) associated to the plasma membrane outer leaflet, ceramide (CER) generation and apoptosis. In the present study, we have investigated the influence of PKCζ , an atypical form of PKC on this pathway. This study shows that PKCζ overexpression resulted in the abrogation of UV-C-induced A-SMase translocation and activation into the raft microdomains, lack of CER generation, and apoptosis inhibition. Moreover, PKCζ overexpression resulted in the reduction of UV-C induced radical oxygen species (ROS) production, which correlated with increased gene expression level of various anti-oxidant enzymes, including thioredoxin (TRx), thioredoxin reductase 1 (TR1), TR2, and peroxiredoxin 1/thioredoxin peroxidase 2 (TPx2). Importantly, enforced-TPx2 gene expression inhibited UV-C induced A-SMase translocation. Finally, PKCζ inhibition led to significant reduction in TPx 2 protein expression level. Altogether, these results suggest that PKCζ interferes with UV-activated sphingolipid signaling pathway by regulating the thioredoxin system. These findings may have important consequences for UV-induced carcinogenesis and resistance to phototherapy.
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