Friday, May 9, 2025
5/9/2025
Deubiquitinating and inhibiting Hsp90 by USP40 mitigates lung injury - Abstract Acute lung injury (ALI) is a life-threatening inflammatory lung condition that is most commonly caused by pneumonia or sepsis. ALI-related mortality remains at unexpectedly high levels. Hence, a new therapeutic strategy for ALI is needed. Uncontrolled cytokine storm, neutrophil influx into alveolar spaces, and leakage from capillaries are the hallmarks of ALI, thus, a promising therapeutic strategy in the acute phase of ALI is to restrain pro-inflammatory responses and capillary barrier disruption simultaneously. Heat shock protein 90 (Hsp90) has been known to contribute to the pathogenesis of ALI by promoting pro-inflammatory responses in a variety of lung cell types and increasing endothelial cell (EC) permeability. Inhibition of Hsp90 activity by small molecule inhibitors have been shown to reduce the severity of ALI in animal models dramatically; however, molecular regulation of Hsp90 has not been well studied. We discovered that Hsp90 can be mono-ubiquitinated and the mono-ubiquitination may compete with acetylation of Hsp90 to increase Hsp90 activity. We identified that USP40, a DUB, deubiquitinates Hsp90, thus resulting in inhibiting Hsp90. We hypothesize that deubiquitinating and inhibiting Hsp90 by USP40 mitigate lung injury by suppressing pro-inflammatory responses and preserving EC barrier integrity. We will determine the molecular mechanisms by which USP40 deubiquitinates and inactivates Hsp90. Then, we will focus on determining the molecular mechanisms by which USP40 mitigates pro-inflammatory responses and pulmonary EC barrier disruption through deubiquitination of Hsp90. Lastly, we will determine if USP40 de-mono-ubiquitination of Hsp90 plays a protective role in murine models of ALI. These studies will be the first to elucidate the protective role of inactivating Hsp90 by USP40 against lung injury.
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