Klotho modulates ER-mediated signaling crosstalk between prosurvival autophagy and apoptotic cell death during LPS challenge
Bacterial endotoxins have been shown to induce prosurvival autophagy or apoptosis in fibroblasts and thus impair the wound healing process. Endoplasmic reticulum has been proposed as a molecular switch between these processes and klotho protein possessing pleiotropic characteristics seems to be involved in both processes, however the exact molecular mechanism is unknown. In this study, we have evaluated the effect of klotho silencing on human fibroblasts exposed to a non-toxic dose of lipopolysaccharide in terms of in vitro wound healing ability. We show for the first time, that klotho silencing in fibroblasts intensified lipopolysaccharide-induced oxidative stress and inflammatory response, what resulted in genomic instability, p-eIF2a-mediated ER stress, retardation of prosurvival autophagy, induction of apoptotic cell death and finally in impaired wound closure. Therefore, our data suggest that klotho serves as a part of cellular defense mechanism engaged in providing protection against bacterial infections during wound healing by modulating ER-signaling crosstalk between autophagy and apoptosis.
KeywordsKlotho Fibroblasts ER stress Autophagy LPS
The authors would like to thank Slawomir Nowak, MSc for providing antibodies against HMOX-1 and HMOX-2.
JM: performed the experiments, analyzed the data, carried out data interpretation, wrote the paper, conceived and designed the experiments; PS: performed the experiments, analyzed the data, carried out data interpretation; MK: conceived and designed the experiments; carried out data interpretation.
Compliance with ethical standards
Conflict of interest
The authors declare no competing interests.
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