A Nonaggregating Surfactant Protein C Mutant Is Misdirected to Early Endosomes and Disrupts Phospholipid Recycling

Interstitial lung disease in both children and adults has been linked to mutations in the lung‐specific surfactant protein C ( SFTPC ) gene. Among these, the missense mutation [isoleucine to threonine at codon 73 = human surfactant protein C (hSP‐C I73T )] accounts for ∼30% of all described SFTPC mutations. We reported previously that unlike the BRICHOS misfolding SFTPC mutants, expression of hSP‐C I73T induces lung remodeling and alveolar lipoproteinosis without a substantial Endoplasmic Reticulum (ER) stress response or ER‐mediated intrinsic apoptosis. We show here that, in contrast to its wild‐type counterpart that is directly routed to lysosomal‐like organelles for processing, SP‐C I73T is misdirected to the plasma membrane and subsequently internalized to the endocytic pathway via early endosomes, leading to the accumulation of abnormally processed proSP‐C isoforms. Functionally, cells expressing hSP‐C I73T demonstrated both impaired uptake and degradation of surfactant phospholipid, thus providing a molecular mechanism for the observed lipid accumulation in patients expressing hSP‐C I73T through the disruption of normal phospholipid recycling. Our data provide evidence for a novel cellular mechanism for conformational protein‐associated diseases and suggest a paradigm for mistargeted proteins involved in the disruption of the endosomal/lysosomal sorting machinery.