HSP90 inhibition modulates NFκB 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-17induced 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 NFκB signaling.Here, we used a targeted phospho-proteomic approach to identify candidate HSP90 clients modulated by the HSP90-inhibitor geldanamycin. NFκB 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 NFκB signaling. We used transcription factor activation, nuclear translocation, and phospho-specific immunofluorescence assays to investigate how IL-13 exposure and HSP90 inhibition modulated NFκB. We found that HSP90 inhibition prevented goblet cell metaplasia by non-canonically blocking NFκB p100/p52 function in human airway epithelia. NFκB 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 mucoinflammatory lung diseases with both known or unidentified disease-driving mechanisms.

Protective role of the HSP90 inhibitor, STA-9090, in lungs of SARS-CoV-2-infected Syrian golden hamsters

“… 16 58 SARS-CoV-2 infection leads to the activation of the IKK, STAT3 and AKT, which activate NF-kB and lead to inflammation. 20 21 26 Production of proinflammatory cytokines, such as IL-1β, IL-6, CXCL10 and TNF, correlated to the progression of COVID-19, were shown to be reduced by HSP90 inhibition, probably due to the role of HSP90 in the NF-kB activation. 33 A reduced inflammation of the lungs also influences the recruitment and activation of important immune cells, which may contribute to tissue damage.…”

“…The pleiotropic effects of HSP90 include degradation of distinct proteins, including MAPK, JAK/STAT and NF-kB, affecting distinct signalling pathways implicated in inflammation, cell proliferation and fibrogenesis 16 58. SARS-CoV-2 infection leads to the activation of the IKK, STAT3 and AKT, which activate NF-kB and lead to inflammation 20 21 26. Production of proinflammatory cytokines, such as IL-1β, IL-6, CXCL10 and TNF, correlated to the progression of COVID-19, were shown to be reduced by HSP90 inhibition, probably due to the role of HSP90 in the NF-kB activation 33.…”

“…The NF-κB protein members, critical in inflammatory signalling pathway, cell proliferation and immune regulation, are important candidate targets of HSP90 and are promptly affected by its inhibition. Moreover, their activation depends on factors also affected by HSP90 inhibition, as IKK 20 21. For its crucial role in stability and function of many oncogenic proteins, pharmacological intervention through HSP90 inhibitors was shown to be beneficial in a wide spectrum of tumour treatment 18 19 22.…”

“…Moreover, their activation depends on factors also affected by HSP90 inhibition, as IKK. 20 21 For its crucial role in stability and function of many oncogenic proteins, pharmacological intervention through HSP90 inhibitors was shown to be beneficial in a wide spectrum of tumour treatment. 18 19 22 Targeting HSP90 was also evaluated in a diverse range of diseases, including neurodegenerative 23 and inflammatory diseases, 24 and infections.…”