Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 138, Issue 7, Pages 1481-1490Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2018.02.002
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Funding
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [AR057216]
- Dermatology Foundation
- Eversight Eye Bank
- National Institutes of Health [EY06769, EY017539, EY019463, DK094980]
- Northwestern Alzheimer's Disease Center Pilot Award [NIA AG13854]
- American Federation for Aging Research New Investigator Award in Alzheimer's Disease
- National Natural Science Foundation of China [31300814, 81673067]
- Natural Science Foundation of Guangdong Province, China [2014A030313319, 2016A020215116]
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We have shown that microRNAs-103 and -107 (miRs-103/107) positively regulate end-stage autophagy by ensuring dynamin activity in cultured keratinocytes. Most work in end-stage autophagy has been conducted using in vitro model systems. In vivo regulation of end-stage autophagy in epidermis remains unknown. Here, we used antagomirs to subcutaneously knock down miR-107 in the skin; conversely, we delivered miR-107 mimic subcutaneously via in vivo transfection to increase this miR. We found that antagomir-107 treatment in epidermis: (i) depleted endogenous miR-107; (ii) increased GFP-LC3 puncta in epidermal basal layers of GFP-LC3 transgenic mice, indicative of an accumulation of autophagosomes; (iii) inhibited LC3 turnover and increased p62, suggesting an inhibition of autophagy flux; and (iv) increased phosphorylated dynamin (p-dynamin, an inactive form), a key enzyme in end-stage autophagy. Conversely, miR-107 mimic treatment in mouse epidermis: decreased GFP-LC3 puncta in basal layer, as well as p62 protein levels; and diminished p-dynamin, indicative of activation of this enzyme. In human epidermal keratinocytes, antagos-103/107 cause the formation of large vacuoles and an increase in p-dynamin, which can be rescued by inhibition of protein kinase C pathway. Collectively, these results suggest that the miR-103/107 family has a critical role in regulating end-stage autophagy in mouse epidermis via PLD1/2-protein kinase C-dynamin pathway.
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