biostudies-literatureKatzen JBLRD VANHLBI NIH HHSe2123187119https://www.ebi.ac.uk/biostudies/studies/S-EPMC9618079biostudies-literatureUnknown119(43)Disruption of alveolar type 2 cell (AEC2) protein quality control has been implicated in chronic lung diseases, including pulmonary fibrosis (PF). We previously reported the in vivo modeling of a clinical surfactant protein C (SP-C) mutation that led to AEC2 endoplasmic reticulum (ER) stress and spontaneous lung fibrosis, providing proof of concept for disruption to proteostasis as a proximal driver of PF. Using two clinical SP-C mutation models, we have now discovered that AEC2s experiencing significant ER stress lose quintessential AEC2 features and develop a reprogrammed cell state that heretofore has been seen only as a response to lung injury. Using single-cell RNA sequencing in vivo and organoid-based modeling, we show that this state arises de novo from intrinsic AEC2 dysfunction. TProceedings of the National Academy of Sciences of the United States of AmericaDisruption of proteostasis causes IRE1 mediated reprogramming of alveolar epithelial cells.PMC9618079K08 HL150226I01 BX005411R01 HL087825I01 BX001176U01 HL134745U01 HL152970R01 HL132999R01 HL152194K08 HL163398R01 HL145408Rodriguez LBeers MFKatzen JCarl JMorley MPelura TRosen GLeach JPMulugeta SZhao MCarson PMurthy AMorrisey EEBabu ABarrett MMcGraw MDTomer YBasil MCfalseDisruption of proteostasis causes IRE1 mediated reprogramming of alveolar epithelial cells.Disruption of alveolar type 2 cell (AEC2) protein quality control has been implicated in chronic lung diseases, including pulmonary fibrosis (PF). We previously reported the in vivo modeling of a clinical surfactant protein C (SP-C) mutation that led to AEC2 endoplasmic reticulum (ER) stress and spontaneous lung fibrosis, providing proof of concept for disruption to proteostasis as a proximal driver of PF. Using two clinical SP-C mutation models, we have now discovered that AEC2s experiencing significant ER stress lose quintessential AEC2 features and develop a reprogrammed cell state that heretofore has been seen only as a response to lung injury. Using single-cell RNA sequencing in vivo and organoid-based modeling, we show that this state arises de novo from intrinsic AEC2 dysfunction. T2022-01-01T00:00:00Z2022 Oct2025-04-04T07:11:09.724Z2025-04-04T07:11:09.724ZS-EPMC96180793625203510.1073/pnas.2123187119