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

作者：Beers Michael F; Hawkins Arie; Maguire Jean Ann; Kotorashvili Adam; Zhao Ming; Newitt Jennifer L; Ding Wenge; Russo Scott; Guttentag Susan; Gonzales Linda; Mulugeta Surafel^*

来源：Traffic, 2011, 12(9): 1196-1210.

DOI：10.1111/j.1600-0854.2011.01223.x

• interstitial lung disease
• lysosomes
• posttranslational processing
• sorting
• surfactant protein C

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-CI73T)] accounts for similar to 30% of all described SFTPC mutations. We reported previously that unlike the BRICHOS misfolding SFTPC mutants, expression of hSP-CI73T 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, SPCI73T 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-CI73T demonstrated both impaired uptake and degradation of surfactant phospholipid, thus providing a molecular mechanism for the observed lipid accumulation in patients expressing hSP-CI73T 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.

• 出版日期2011-9