Goblet cell metaplasia and mucus hyper-production are key features of chronic muco-obstructive lung diseases such as asthma, chronic bronchitis, and cystic fibrosis. Various mechanisms lead to goblet cell metaplasia in the airways; the driving mechanism for goblet cell metaplasia in a specific patient may be unknown. We recently found that heat shock protein 90 (HSP90) is important for both IL-13- and IL-17-induced airway goblet cell metaplasia. HSP90 interacts with multiple clients that are important in goblet cell metaplasia including Akt, Jak/STAT, IRS, Notch, and various kinases involved in NFB signaling. Here, we used a targeted phospho-proteomic approach to identify candidate HSP90 clients modulated by the HSP90-inhibitor geldanamycin. NFB family members were enriched amongst the top candidate targets of HSP90 inhibition in IL-13 an organotypic model of human airway epithelia. We hypothesized that HSP90 inhibition modulated goblet cell metaplasia by interfering with NFB signaling. We used transcription factor activation, nuclear translocation, and phospho-specific immunofluorescence assays to investigate how IL-13 exposure and HSP90 inhibition modulated NFB. We found that HSP90 inhibition prevented goblet cell metaplasia by non-canonically blocking NFB p100/p52 function in human airway epithelia. NFB modulation via its interaction with HSP90 is a pharmaceutically feasible therapeutic target for goblet cell metaplasia; this approach may enable treatment of patients with chronic muco-inflammatory lung diseases with both known or unidentified disease-driving mechanisms.

中文翻译：

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HSP90抑制调节气道杯状细胞化生中的NFB信号传导

杯状细胞化生和粘液过度产生是慢性粘膜阻塞性肺病（例如哮喘，慢性支气管炎和囊性纤维化）的关键特征。多种机制导致气道中的杯状细胞化生。在特定患者中杯状细胞化生的驱动机制可能是未知的。我们最近发现，热休克蛋白90（HSP90）对于IL-13和IL-17诱导的气道杯状细胞化生都很重要。HSP90与在杯状细胞化生中重要的多个客户进行交互，包括Akt，Jak / STAT，IRS，Notch以及涉及NFB信号传导的各种激酶。在这里，我们使用了靶向的磷酸化蛋白质组学方法来鉴定由HSP90抑制剂格尔德霉素调节的候选HSP90客户。在人气道上皮细胞器官模型IL-13中，NFB家族成员富集了HSP90抑制的最佳候选靶点。我们假设HSP90抑制通过干扰NFB信号传导调节杯状细胞的化生。我们使用了转录因子激活，核易位和磷酸特异性免疫荧光分析法来研究IL-13暴露和HSP90抑制作用如何调节NFB。我们发现HSP90抑制通过非规范性阻断人类气道上皮中的NFB p100 / p52功能来防止杯状细胞化生。通过与HSP90相互作用而调节NFB是杯状细胞化生的药学上可行的治疗靶点；这种方法可以通过已知或未知的疾病驱动机制治疗慢性粘膜炎性肺疾病。