Role of VAPA-mediated membrane contact sites in lung surfactant production

• Applicant: Professor Dr. Matias Simons
• Subject Area: Cell Biology ; Pneumology, Thoracic Surgery
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568716442

VAPA and VAPB, two ER-resident proteins, are prominent tethering proteins playing key roles in membrane contact site (MCS) formation. They act as general receptors for hundreds of proteins containing a FFAT motif, through their Major Sperm Protein (MSP) domains. By using molecular and cellular approaches, we and others have demonstrated that VAP interactions with FFAT-containing lipid-transfer proteins tether membranes and regulate lipid transport and metabolic pathways, thereby enabling essential cell homeostatic functions. Using exome sequencing, we recently identified a homozygous nonsense mutation in the VAPA gene (p.E12X) of a child patient in our genetics clinic. The patient shows progressive surfactant-deficient pulmonary fibrosis as predominant phenotype, thereby raising critical questions about VAPA role in lung health. Therefore, the VAPA-SURF project will delve into an unexplored branch of VAP-mediated contact sites that may be crucial in the formation and maturation of lamellar bodies (LBs)—specialized organelles in alveolar cells responsible for producing lung surfactant. These LBs contain densely packed membrane layers rich in surfactant lipids, yet how neosynthesized surfactant lipids reach the developing LB is a largely overlooked issue. Investigating the role of VAPA in LB biogenesis could provide novel insights into the molecular mechanisms underpinning surfactant metabolism, lung function and diseases.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Bruno Mesmin, Ph.D.