title: A nonaggregating surfactant protein C mutant is misdirected to early endosomes and disrupts phospholipid recycling.
abstract: 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.
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Beers
authors.forename: Arie
authors.initials: A
authors.lastname: Hawkins
authors.forename: Jean Ann
authors.initials: JA
authors.lastname: Maguire
authors.forename: Adam
authors.initials: A
authors.lastname: Kotorashvili
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Newitt
authors.forename: Wenge
authors.initials: W
authors.lastname: Ding
authors.forename: Scott
authors.initials: S
authors.lastname: Russo
authors.forename: Susan
authors.initials: S
authors.lastname: Guttentag
authors.forename: Linda
authors.initials: L
authors.lastname: Gonzales
authors.forename: Surafel
authors.initials: S
authors.lastname: Mulugeta
mesh_terms: D000328:Adult; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D004705:Endocytosis / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D011992:Endosomes / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008247:Lysosomes / Q000378:metabolism; D009154:Mutation; D010743:Phospholipids / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism
chemical_list: D010743:Phospholipids; D020033:Protein Isoforms; D011498:Protein Precursors; D037721:Pulmonary Surfactant-Associated Protein C; D011993:Recombinant Fusion Proteins; D014168:Transferrin