title: Impaired Lysosomal Integral Membrane Protein 2-dependent Peroxiredoxin 6 Delivery to Lamellar Bodies Accounts for Altered Alveolar Phospholipid Content in Adaptor Protein-3-deficient pearl Mice.
abstract: The Hermansky Pudlak syndromes (HPS) constitute a family of disorders characterized by oculocutaneous albinism and bleeding diathesis, often associated with lethal lung fibrosis. HPS results from mutations in genes of membrane trafficking complexes that facilitate delivery of cargo to lysosome-related organelles. Among the affected lysosome-related organelles are lamellar bodies (LB) within alveolar type 2 cells (AT2) in which surfactant components are assembled, modified, and stored. AT2 from HPS patients and mouse models of HPS exhibit enlarged LB with increased phospholipid content, but the mechanism underlying these defects is unknown. We now show that AT2 in the pearl mouse model of HPS type 2 lacking the adaptor protein 3 complex (AP-3) fails to accumulate the soluble enzyme peroxiredoxin 6 (PRDX6) in LB. This defect reflects impaired AP-3-dependent trafficking of PRDX6 to LB, because pearl mouse AT2 cells harbor a normal total PRDX6 content. AP-3-dependent targeting of PRDX6 to LB requires the transmembrane protein LIMP-2/SCARB2, a known AP-3-dependent cargo protein that functions as a carrier for lysosomal proteins in other cell types. Depletion of LB PRDX6 in AP-3- or LIMP-2/SCARB2-deficient mice correlates with phospholipid accumulation in lamellar bodies and with defective intraluminal degradation of LB disaturated phosphatidylcholine. Furthermore, AP-3-dependent LB targeting is facilitated by protein/protein interaction between LIMP-2/SCARB2 and PRDX6 in vitro and in vivo Our data provide the first evidence for an AP-3-dependent cargo protein required for the maturation of LB in AT2 and suggest that the loss of PRDX6 activity contributes to the pathogenic changes in LB phospholipid homeostasis found HPS2 patients.
authors.affiliation: From the Division of Neonatology and.
authors.forename: Seunghyi
authors.initials: S
authors.lastname: Kook
authors.affiliation: From the Division of Neonatology and.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Division of Pediatric Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Young
authors.affiliation: the Department of Chemistry, Biochemistry III, University of Bielefeld, D-33615 Bielefeld, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwake
authors.affiliation: the Institute of Biochemistry, Christian-Albrechts-University, Olshausenstrasse 40, D-24098 Kiel, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.affiliation: the Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, China.
authors.forename: Xialian
authors.initials: X
authors.lastname: Weng
authors.affiliation: the Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Meng
authors.affiliation: the Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, China.
authors.forename: Dante
authors.initials: D
authors.lastname: Neculai
authors.affiliation: the Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, and the Departments of Pathology and Laboratory Medicine and of Physiology, and.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Marks
authors.affiliation: Division of Adult Pulmonary and Critical Care Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Linda
authors.initials: L
authors.lastname: Gonzales
authors.affiliation: Division of Adult Pulmonary and Critical Care Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Beers
authors.affiliation: From the Division of Neonatology and susan.guttentag@vanderbilt.edu.
authors.forename: Susan
authors.initials: S
authors.lastname: Guttentag
mesh_terms: D033963:Adaptor Protein Complex 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D005260:Female; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D054465:Peroxiredoxin VI / Q000235:genetics / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology
chemical_list: D033963:Adaptor Protein Complex 3; D018955:CD36 Antigens; D051907:Lysosomal Membrane Proteins; D010713:Phosphatidylcholines; C489452:Scarb2 protein, mouse; D054465:Peroxiredoxin VI; C515983:Prdx6 protein, mouse
keywords: AP-3; Hermansky Pudlak syndrome; adaptor protein; alveolar epithelial type 2 cell; lamellar body; lung; peroxiredoxin; peroxiredoxin 6; phospholipid metabolism; trafficking