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Impairment of epithelial cell endocytosis by mistargeted SP‐C I73T mutant protein
Author(s) -
Hawkins Arie Ellen,
Zhao Ming,
Beers Michael F.,
Mulugeta Surafel
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.865.12
Subject(s) - endocytosis , endosome , hek 293 cells , endocytic cycle , internalization , microbiology and biotechnology , wild type , mutant , mutation , biology , cell , cell culture , chemistry , intracellular , biochemistry , genetics , gene
Interstitial lung disease in both children and adults has been linked to mutations in the lung‐ specific Surfactant Protein C (SP‐C) proprotein. Among these, the missense mutation, SP‐C I73T , accounts for more than 30% of all reported SP‐C mutations. We previously reported that in A549 and HEK293 cell lines, wild type SP‐C was directly targeted to lysosomal‐like vesicles, while SP‐C I73T was uncharacteristically routed to the plasma membrane, and subsequently sorted to the lysosomes via early endosomes. This mistargeting causes impaired cellular lipid uptake and degradation. To determine whether the diminution of lipid uptake is the product of a globally dysfunctional endocytic pathway, cellular uptake of dextran was examined in HEK293 cells stably expressing either the wild type or the mutant SP‐C isoforms. We found that internalization of dextran was significantly reduced in cells expressing SP‐C I73T compared to the wild type control. Thus, our data further establishes the functional impairment caused by the SP‐C I73T mutation, and supports our previously proposed cellular mechanism and paradigm for mistargeted proteins involved in the disruption of endosomal/lysosomal sorting machinery. Supported By NIH HL090732 (SM), NIH HL19737 (MFB)