A nonaggregating surfactant protein C mutant is misdirected to early endosomes and disrupts phospholipid recycling.

Beers MF, Hawkins A, Maguire JA, Kotorashvili A, Zhao M, Newitt JL, Ding W, Russo S, Guttentag S, Gonzales L, Mulugeta S
Traffic. 2011 12 (9): 1196-210

PMID: 21707890 · PMCID: PMC3155663 · DOI:10.1111/j.1600-0854.2011.01223.x

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.

© 2011 John Wiley & Sons A/S.

MeSH Terms (19)

Adult Cell Membrane Cells, Cultured Child Endocytosis Endoplasmic Reticulum Endosomes Humans Lung Diseases, Interstitial Lysosomes Mutation Phospholipids Protein Isoforms Protein Precursors Protein Transport Pulmonary Surfactant-Associated Protein C Recombinant Fusion Proteins Transferrin Transport Vesicles

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