Ph.D Students Kangwon National University, Republic of Korea
Abstract: Interstitial lung disease (ILD) is a progressive pulmonary disease characterized by inflammation and fibrosis in the lung parenchyma, often driven by dysfunction of alveolar type 2 epithelial cells (AT2s). Surfactant protein C (SFTPC), produced exclusively by AT2s, plays a critical role in maintaining lung homeostasis by regulating the surface tension of pulmonary fluids. However, mutations in SFTPC, particularly I73T, lead to its misfolding and toxic accumulation, triggering subsequent pulmonary fibrosis (PF) associated with toxic gain of function. Although the association between mutant SFTPC and fibrosis is well established, the mechanism regulating its stability remains poorly understood. In this study, we aimed to provide a detailed understanding of the mechanism that regulates the stability of the SFTPCI73T mutant protein during the progression of PF and to suggest a novel therapeutic approach for fibrosis. To address this, we identified USP11 as a novel deubiquitinase (DUB), which is an important protein stabilizer of SFTPC, and confirmed the strong interaction including the deubiquitinating and stabilizing effect on SFTPCI73T mutant protein. To mimic SFTPCI73T-induced fibrosis, we generated human induced pluripotent stem cell (hiPSC)-derived alveolar organoids (AOs) carrying the I73T mutation and successfully recapitulated key fibrotic features. Interestingly, we confirmed that the spontaneous fibrotic changes caused by the mutation were significantly attenuated by the reduction of USP11. Furthermore, we demonstrated that pharmacological inhibition of USP11 alleviates the fibrotic lesions of PF in hiPSCs-SFTPCI73T-AOs and BLM-induced mouse model, underscoring its therapeutic potential. Our study establishes a novel ILD model using gene-edited hiPSC-derived AOs and paves the way for targeted treatment of PF by regulating SFTPC stability through USP11 inhibition, suggesting a novel therapeutic strategy for patients with PF.
Funding Source: This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (RS-2022-NR067319).
