VAPA-dependent lipid transport in alveolar epithelial type 2 cells promotes lung surfactant formation

VAP proteins form membrane contact sites (MCS) between the endoplasmic reticulum (ER) and other organelles through interactions with FFAT-containing proteins, thereby coordinating lipid synthesis, transfer, and metabolism. However, their tissue-specific functions remain largely unexplored. Here, we report the first patient with a homozygous nonsense variant in VAPA (p.(Glu12*)), presenting with profound global developmental delay and progressive surfactant dysfunction leading to cholesterol pneumonitis and pulmonary fibrosis. Alternative translation initiation partially bypasses the premature stop codon, resulting in an N-terminally truncated VAPA protein with impaired FFAT-binding capacity. In alveolar type 2 cells, VAPA deficiency impairs lamellar body (LB) formation. We identify the pulmonary disease-associated ATP-binding cassette transporter A3 (ABCA3), a key regulator of surfactant lipid accumulation in LBs, as a novel VAPA interactor. The VAPA–ABCA3 interaction facilitates lipid exchange at previously uncharacterized ER–LB MCS, a function that is lost upon N-terminal truncation of VAPA. Together, our findings identify impaired VAPA-dependent MCS function as a mechanism underlying syndromic lung disease and reveal a previously unrecognized pathway for surfactant lipid trafficking.

• Type: RNASeq
• Archive: European Genome-phenome Archive (EGA)