PKCzeta protects against UV-C-induced apoptosis by inhibiting acid sphingomyelinase-dependent ceramide production.
In a recent study, we described that UV-C irradiation resulted in redox-dependent activation and relocalization of A-SMase (acid sphingomyelinase) to the external surface of raft membrane microdomains, hydrolysis of SM (sphingomyelin) associated with the plasma membrane outer leaflet, ceramide generation and apoptosis. In the present study, we have investigated the influence of PKCzeta (protein kinase Czeta), an atypical form of PKC on this pathway. This study shows that PKCzeta overexpression resulted in the abrogation of UV-C-induced A-SMase translocation and activation into the raft microdomains, lack of ceramide generation and apoptosis inhibition. Moreover, PKCzeta overexpression resulted in a decrease in UV-C-induced ROS (reactive oxygen species) production, which correlated with increased gene expression level of various antioxidant enzymes, including TRx (thioredoxin), TR (thioredoxin reductase) 1, TR2 and peroxiredoxin 1/TPx2 (thioredoxin peroxidase 2). Importantly, enforced TPx2 gene expression inhibited UV-C-induced A-SMase translocation. Finally, PKCzeta inhibition led to a significant reduction in TPx2 protein expression. Altogether, these results suggest that PKCzeta interferes with the UV-activated sphingolipid signalling pathway by regulating the TRx system. These findings may have important consequences for UV-induced carcinogenesis and resistance to phototherapy.
Charruyer
Alexandra
A
Inserm, U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, F-31300, France.
Jean
Christine
C
Colomba
Audrey
A
Jaffrézou
Jean-Pierre
JP
Quillet-Mary
Anne
A
Laurent
Guy
G
Bezombes
Christine
C
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D002460:Cell Line; D002518:Ceramides / Q000096:biosynthesis*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D014466:Ultraviolet Rays; D000099221:Protein Kinase C zeta
D002518:Ceramides; D006861:Hydrogen Peroxide; D016877:Oxidants; D011493:Protein Kinase C; D017382:Reactive Oxygen Species; D013108:Sphingomyelin Phosphodiesterase; D013879:Thioredoxins; D000099221:Protein Kinase C zeta