Autophagy Negatively Regulates Keratinocyte Inflammatory Responses via Scaffolding Protein p62/SQSTM1
Autophagy Negatively Regulates Keratinocyte Inflammatory Responses via Scaffolding Protein p62/SQSTM1
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DOI：
10.4049/jimmunol.1001954
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发表时间：
2011-01-15
影响因子：
4.4
通讯作者：
Jo, Eun-Kyeong
中科院分区：
文献类型：
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作者：
Lee, Hye-Mi;Shin, Dong-Min;Jo, Eun-Kyeong
支架衔接蛋白p62/SQSTM1（p62）已被证明是一种自噬受体，它在泛素化机制和自噬机制之间起到连接作用。然而，自噬和p62在人角质形成细胞中的作用尚未被充分了解。在本研究中，我们发现角质形成细胞自噬对p62表达起负调控作用，这对于预防人角质形成细胞中过度炎症以及诱导抗菌肽的产生至关重要。在原代人角质形成细胞中刺激TLR2/6或TLR4可强烈激活自噬途径，并通过诱导NADPH氧化酶2和4以及活性氧的产生而上调p62表达。MyD88和TNFR相关因子6是介导TLR激活的关键信号分子，它们在诱导自噬和p62表达中起重要作用。此外，阻断自噬可显著增加原代人角质形成细胞中炎性细胞因子的产生和p62的表达。值得注意的是，通过RNA干扰沉默hp62可导致角质形成细胞中NF - κB激活、炎性细胞因子产生、抗菌肽表达以及细胞增殖（以及细胞周期蛋白D1表达）显著降低。进一步发现p62在银屑病皮肤中的表皮表达明显高于特应性皮炎受累皮肤或健康对照皮肤。总之，我们的数据为自噬和p62在控制皮肤炎症中的作用提供了新的见解。《免疫学杂志》，2011年，186卷：1248 - 1258页。
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-kappa B 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. The Journal of Immunology, 2011, 186: 1248-1258.