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

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.

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.

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.

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.