Autophagy negatively regulates keratinocyte inflammatory responses via scaffolding protein p62/SQSTM1.

Abstract

The scaffolding adaptor protein p62/SQSTM1 (p62) has been shown to be an autophagy receptor that acts as a link between the ubiquitination and autophagy machineries. However, the roles of autophagy and p62 in human keratinocytes are not well understood. In this study, we show that keratinocyte autophagy negatively regulates p62 expression, which is essential for the prevention of excessive inflammation and the induction of cathelicidin in human keratinocytes. Stimulation of TLR2/6 or TLR4 in primary human keratinocytes robustly activated autophagy pathways and up-regulated p62 expression through induction of NADPH oxidases 2 and 4 and the generation of reactive oxygen species. MyD88 and TNFR-associated factor 6, key signaling molecules that mediate TLR activation, played an essential role in the induction of autophagy and p62 expression. Additionally, blockade of autophagy significantly increased the generation of inflammatory cytokines and expression of p62 in primary human keratinocytes. Notably, silencing hp62 through RNA interference resulted in a significant decrease in NF-κB activation, inflammatory cytokine production, cathelicidin expression, and cell proliferation (as well as cyclin D1 expression) in keratinocytes. Epidermal expression of p62 was further found to be significantly higher in psoriatic skin than in skin affected by atopic dermatitis or from healthy controls. Collectively, our data provide new insights into the roles of autophagy and p62 in controlling cutaneous inflammation.

• Authors: Hye-Mi Lee, Dong-Min Shin, Jae-Min Yuk, Ge Shi, Dae-Kyoung Choi, Sang-Hee Lee, Song Mei Huang, Jin-Man Kim, Chang Deok Kim, Jeung-Hoon Lee, Eun-Kyeong Jo
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 186 Issue 2 Pg. 1248-58 (Jan 15 2011) ISSN: 1550-6606 [Electronic] United States
• PMID: 21160040 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antimicrobial Cationic Peptides
• Cytokines
• Inflammation Mediators
• NF-kappa B
• Reactive Oxygen Species
• SQSTM1 protein, human
• Sequestosome-1 Protein
• TLR2 protein, human
• TLR6 protein, human
• Toll-Like Receptor 2
• Toll-Like Receptor 6
• Cathelicidins

Topics

• Adaptor Proteins, Signal Transducing (biosynthesis, physiology)
• Antimicrobial Cationic Peptides (biosynthesis)
• Autophagy (immunology)
• Cell Line
• Cytokines (biosynthesis)
• Dermatitis, Atopic (immunology, metabolism, pathology)
• Down-Regulation (immunology)
• HEK293 Cells
• Humans
• Inflammation Mediators (physiology)
• Keratinocytes (immunology, metabolism, pathology)
• NF-kappa B (physiology)
• Psoriasis (immunology, metabolism, pathology)
• Reactive Oxygen Species (metabolism)
• Sequestosome-1 Protein
• Toll-Like Receptor 2 (metabolism, physiology)
• Toll-Like Receptor 6 (metabolism, physiology)
• Cathelicidins