HSP90 inhibition modulates NFB signaling in airway goblet cell metaplasia

Abstract

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 NF{kappa}B signaling. Here, we used a targeted phospho-proteomic approach to identify candidate HSP90 clients modulated by the HSP90-inhibitor geldanamycin. NF{kappa}B 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 NF{kappa}B signaling. We used transcription factor activation, nuclear translocation, and phospho-specific immunofluorescence assays to investigate how IL-13 exposure and HSP90 inhibition modulated NF{kappa}B. We found that HSP90 inhibition prevented goblet cell metaplasia by non-canonically blocking NF{kappa}B p100/p52 function in human airway epithelia. NF{kappa}B 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.