Abstract
Autophagy is a cellular catabolic mechanism that is activated in response to stress conditions, including ultraviolet (UV) irradiation, starvation, and misfolded protein accumulation. Abnormalities in autophagy are associated with several pathologies, including aging and cancer. Furthermore, recent studies have demonstrated that microRNAs (miRNAs) are potent modulators of the autophagy pathway. As a result, the current study aims to elucidate the role of the autophagy-related miRNA miR-23ain the process of photoaging. Experiments demonstrated that the antagomir-mediated inactivation of miR-23a resulted in the stimulation of PUVA- and UVB-depressed autophagy flux and protected human fibroblasts from premature senescence. Furthermore, AMBRA1 was identified as a miR-23a target. AMBRA1 cellular levels increased following the introduction of miR-23a antagomirs. And a bioinformatics analysis revealed that the AMBRA1 3′ UTR contains functional miR-23a responsive sequences. Finally, it was also demonstrated that both AMBRA1 overexpression and Rapamycin treatment were both able to rescue fibroblasts from PUVA and UVB irradiation-induced autophagy inhibition, but that these effects could also be mitigated by miR-23a overexpression. Therefore, this study concludes that miR-23a-regulated autophagy is a novel and important regulator of ultraviolet-induced premature senescence and AMBRA1 is a rate-limiting miRNA target in this pathway.
Highlights
Chronic exposure to solar ultraviolet radiation (UV) can induce photoaging [1]
It was demonstrated that both AMBRA1 overexpression and Rapamycin treatment were both able to rescue fibroblasts from plus ultraviolet-A irradiation (PUVA) and UVB irradiation-induced autophagy inhibition, but that these effects could be mitigated by miR-23a overexpression
Confocal microscopy revealed that PUVA and UVB irradiation could repress GFP-LC3 puncta formation in fibroblasts, indicating that autophagy is inhibited under these conditions (Figure 1a-1b)
Summary
Ex vivo experiments have shown that the repeated exposures of human skin fibroblasts to UVB or 8-methoxypsoralen plus ultraviolet-A irradiation (PUVA) at subcytotoxic levels triggers ultraviolet stress-induced premature senescence (SIPS) [2, 3]. Under these conditions, fibroblasts cease to divide, and instead undergo a series of dramatic morphological and metabolic changes [4]. The dynamic process of degrading unnecessary or dysfunctional cell components, has been linked to aging [6]. The underlying molecular mechanism linking autophagy to photoaging is still not known
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