Autophagy pathways activated in response to PDT contribute to cell resistance against ROS damage.
Bottom Line: Paradoxically, genetic loss of MA improved clearance of oxidized proteins and reduced photokilling.We found that up-regulation of chaperone-mediated autophagy (CMA) in unstressed Atg(-/-) cells compensated for MA loss and increased cellular resistance to PDT.These results disclose a stress-specific recruitment of autophagy pathways with cytoprotective function and unravel CMA as the dominant defence mechanism against PDT.
Affiliation: Cell Death Research and Therapy Laboratory, Department of Molecular Cell Biology, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.Show MeSH
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Mentions: Whereas MA attenuation by siRNA-Atg5 knockdown or 3MA increased photokilling, MA-deficiency surprisingly prevented mitochondrial cytochrome c release, caspase 3 processing, PARP cleavage and apoptosis (Fig. 4A and B) as well as overall cell death (Fig. S3A, right panel). Evaluation of phosphatidylserine exposure through annexinV-FITC labelling and cell survival within a wide range of PDT doses, confirmed that Atg5−/− MEFs survived better following PDT (Fig. 4C and D). Furthermore, the cytoprotective effect of MA-deficiency against photokilling was substantiated by examining the response of RasV12 transformed WT and Atg5-KO MEFs after PDT (Fig. S4A and B), thus indicating that protection against ROS-induced apoptosis by MA loss occurs both in normal and transformed cells. Remarkably, along with the decreased apoptotic signalling, photosensitized Atg5−/− cells demonstrated an enhanced clearance of oxidized proteins as compared to their WT counterparts (Fig. 5A).
Affiliation: Cell Death Research and Therapy Laboratory, Department of Molecular Cell Biology, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.