Abstract
Proteasomes are a critical component of quality control that regulate turnover of short-lived, unfolded, and misfolded proteins. Proteasome activity has been therapeutically targeted and considered as a treatment option for several chronic lung disorders including pulmonary fibrosis. Although pharmacologic inhibition of proteasome activity effectively prevents the transformation of fibroblasts to myofibroblasts, the effect on alveolar type 2 (AT2) epithelial cells is not clear. To address this knowledge gap, we generated a genetic model in which a proteasome subunit, RPT3, which promotes assembly of active 26S proteasome, was conditionally deleted in AT2 cells of mice. Partial deletion of RPT3 resulted in 26S proteasome dysfunction, leading to augmented cell stress and cell death. Acute loss of AT2 cells resulted in depletion of alveolar surfactant, disruption of the alveolar epithelial barrier and, ultimately, lethal acute respiratory distress syndrome (ARDS). This study underscores importance of proteasome function in maintenance of AT2 cell homeostasis and supports the need to further investigate the role of proteasome dysfunction in ARDS pathogenesis.
Highlights
Cellular quality control (QC) is governed by two distinct but interconnected processes, the ubiquitin-proteasome system and the autophagy-lysosome system[1]
Consistent with the degenerative phenotypes observed in RPT3-deficient mice, we hypothesized that RPT3 deficiency in alveolar type 2 (AT2) cells would predispose to fibrosis, i.e. proteasome dysfunction would result in formation and accumulation of aggregates, resulting in chronic AT2 cell injury and a persistent fibroproliferative response
RPT3 was conditionally deleted from AT2 cells by crossing RPT3F/F mice with Sftpc-CreERT2 driver mice and feeding 8-12-week old female and male SftpcWT/CreER:RPT3F/F mice tamoxifen chow for 7 days
Summary
Cellular quality control (QC) is governed by two distinct but interconnected processes, the ubiquitin-proteasome system and the autophagy-lysosome system[1]. The therapeutic use of proteasome inhibitors is further complicated by reports that some patients treated with Bortezomib developed significant pulmonary complications including acute respiratory distress syndrome (ARDS)[8,9,10,11,12]. These data underscore the need to further investigate the use of proteasome inhibitors in chronic lung diseases, including identification of potential cell-specific responses to proteasome inhibition. These findings suggest that the risk of respiratory failure is a concern for some patients undergoing high dose and/or extended proteasome inhibitor therapy
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