SDPR-STK38 axis controls the proliferation-differentiation balance in alveolar type II cells.

Abstract

Background: Alveolar type II (AT2) cells act as progenitors that sustain gas exchange and drive postinjury repair. Disruption of their proliferation-differentiation balance promotes pulmonary fibrosis and acute respiratory distress syndrome, but the core regulatory mechanisms are unclear. Serum deprivation response protein (SDPR, cavin-2), a caveolae-associated protein involved in proliferation and lipid metabolism, may modulate AT2 fate. This study investigated how the SDPR-STK38 axis regulates AT2 proliferation and differentiation and its impact on lung homeostasis and regeneration.

Methods: SDPR knockout (SDPR^{- / -}) mice and wild-type littermates were used to evaluate alveolar structure, AT2/AT1 composition, and lung function at baseline and after LPS-induced acute lung injury. Histology, immunostaining, and lung function tests were combined with mass spectrometry and co-immunoprecipitation to identify SDPR-interacting proteins. Gain- and loss-of-function assays in lung tissues and cells were used to assess how SDPR and STK38 regulate GSK-3β/cyclin D1 signaling and Notch-Hes1-dependent AT2 differentiation. Data were analyzed using standard statistical tests appropriate for the experimental design.

Results: SDPR deficiency disrupted alveolar architecture and impaired lung function, accompanied by excessive AT2 expansion and reduced differentiation into AT1 cells. Proteomic and biochemical analyses identified STK38 as a novel SDPR-binding protein. SDPR loss increased STK38 expression, enhanced GSK-3β/cyclin D1 signaling, and promoted AT2 proliferation, while simultaneously reducing Hes1 expression, impairing vacuole formation, and attenuating AT2 differentiation. In the LPS model, SDPR^{- / -} mice developed more severe pathological injury and declined lung function compared to wild-type controls.

Conclusions: The SDPR-STK38 axis coordinately controls the proliferation-differentiation balance of AT2 cells via GSK-3β/cyclin D1 and Notch-Hes1 signaling. SDPR deficiency drives aberrant AT2 expansion, blocks differentiation toward AT1 cells, and aggravates acute lung injury, highlighting this pathway as a potential therapeutic target for promoting alveolar regeneration.