FRA1:c-JUN:HDAC1 complex down-regulates filaggrin expression upon TNFα and IFNγ stimulation in keratinocytes.
FRA1:c-JUN:HDAC1 complex down-regulates filaggrin expression upon TNFα and IFNγ stimulation in keratinocytes.
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DOI：
10.1073/pnas.2123451119
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发表时间：
2022-09-13
影响因子：
11.1
通讯作者：
Shin, Soon Young
中科院分区：
文献类型：
--
作者：
Ahn, Sung Shin;Yeo, Hyunjin;Jung, Euitaek;Lim, Yoongho;Lee, Young Han;Shin, Soon Young
聚丝蛋白 (FLG) 是皮肤屏障功能的结构蛋白之一。 FLG 表达减少与炎症性皮肤病（例如特应性皮炎和牛皮癣）的发病机制有关。然而，目前尚不清楚FLG如何在转录水平上下调。在本研究中，我们发现AP1的FRA1和c-JUN成分与组蛋白脱乙酰酶1相互作用形成阻遏复合物，在肿瘤坏死因子α（TNFα）+干扰素（IFNγ）刺激下角质形成细胞中下调FLG启动子活性。阻断这种复合物可能对炎症性皮肤病患者有治疗作用。聚丝蛋白 (FLG) 是皮肤屏障功能的重要结构蛋白，在慢性炎症条件下会下调，导致皮肤屏障破坏。然而，人们对 FLG 在慢性炎症背景下如何变化的详细分子机制知之甚少。在这里，我们确定了炎症细胞因子抑制皮肤中 FLG 表达的分子机制。我们发现 FLG 启动子的 –343/+25 内的 AP1 响应元件对于 TNFα + IFNγ 诱导的 FLG 启动子活性下调是必需的。使用 DNA 亲和沉淀测定，我们观察到响应 TNFα + IFNγ 刺激，与 FLG 启动子结合的 AP1 亚基组成从 c-FOS:c-JUN（早期）改变为 FRA1:c-JUN（晚期）。 FRA1 或 c-JUN 的敲低消除了 TNFα + IFNγ 诱导的 FLG 抑制。组蛋白脱乙酰酶 (HDAC) 1 在 TNFα + IFNγ 刺激下与 FRA1:c-JUN 相互作用。 HDAC1 的敲低消除了 TNFα + IFNγ 对 FLG 表达的抑制作用。 FLG、FRA1、c-JUN 和 HDAC1 表达的改变在 2,4-二硝基氯苯诱导的特应性皮炎和咪喹莫特诱导的牛皮癣小鼠模型中得到证实。因此，目前的研究表明，TNFα + IFNγ 刺激通过促进 FRA1:c-JUN:HDAC1 复合物抑制 FLG 表达。这项研究为未来针对 FRA1:c-JUN:HDAC1 复合物的治疗策略提供了见解，以恢复慢性皮肤炎症中受损的 FLG 表达。
Filaggrin (FLG) is one of the structural proteins for skin barrier function. Reduced FLG expression is implicated in the pathogenesis of inflammatory skin diseases, such as atopic dermatitis and psoriasis. However, it remains unclear how FLG is down-regulated at the transcriptional level. In this study, we found that the FRA1 and c-JUN components of AP1 interact with histone deacetylase 1 to form a repressor complex that down-regulates FLG promoter activity under tumor necrosis factor α (TNFα) + interferon (IFNγ) stimulation in keratinocytes. Blocking this complex may have therapeutic benefits in patients with inflammatory skin diseases. Filaggrin (FLG), an essential structural protein for skin barrier function, is down-regulated under chronic inflammatory conditions, leading to disruption of the skin barrier. However, the detailed molecular mechanisms of how FLG changes in the context of chronic inflammation are poorly understood. Here, we identified the molecular mechanisms by which inflammatory cytokines inhibit FLG expression in the skin. We found that the AP1 response element within the –343/+25 of the FLG promoter was necessary for TNFα + IFNγ–induced down-regulation of FLG promoter activity. Using DNA affinity precipitation assay, we observed that AP1 subunit composition binding to the FLG promoter was altered from c-FOS:c-JUN (at the early time) to FRA1:c-JUN (at the late time) in response to TNFα + IFNγ stimulation. Knockdown of FRA1 or c-JUN abrogated TNFα + IFNγ–induced FLG suppression. Histone deacetylase (HDAC) 1 interacted with FRA1:c-JUN under TNFα + IFNγ stimulation. Knockdown of HDAC1 abrogated the inhibitory effect of TNFα + IFNγ on FLG expression. The altered expression of FLG, FRA1, c-JUN, and HDAC1 was confirmed in mouse models of 2,4-dinitrochlorobenzene–induced atopic dermatitis and imiquimod-induced psoriasis. Thus, the current study demonstrates that TNFα + IFNγ stimulation suppresses FLG expression by promoting the FRA1:c-JUN:HDAC1 complex. This study provides insight into future therapeutic strategies targeting the FRA1:c-JUN:HDAC1 complex to restore impaired FLG expression in chronic skin inflammation.
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1.6
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