title: Annexin A2 mediates secretion of collagen VI, pulmonary elasticity and apoptosis of bronchial epithelial cells.
abstract: The annexins are an evolutionarily conserved family of phospholipid-binding proteins of largely unknown function. We observed that the AnxA2(-/-) lung basement membrane specifically lacks collagen VI (COL6), and postulated that ANXA2 directs bronchial epithelial cell secretion of COL6, an unusually large multimeric protein. COL6 serves to anchor cells to basement membranes and, unlike other collagens, undergoes multimerization prior to secretion. Here, we show that AnxA2(-/-) mice have reduced exercise tolerance with impaired lung tissue elasticity, which was phenocopied in Col6a1(-/-) mice. In vitro, AnxA2(-/-) fibroblasts retained COL6 within intracellular vesicles and adhered poorly to their matrix unless ANXA2 expression was restored. In vivo, AnxA2(-/-) bronchial epithelial cells underwent apoptosis and disadhesion. Immunoprecipitation and immunoelectron microscopy revealed that ANXA2 associates with COL6 and the SNARE proteins SNAP-23 and VAMP2 at secretory vesicle membranes of bronchial epithelial cells, and that absence of ANXA2 leads to retention of COL6 in a late-Golgi, VAMP2-positive compartment. These results define a new role for ANXA2 in the COL6 secretion pathway, and further show that this pathway establishes cell-matrix interactions that underlie normal pulmonary function and epithelial cell survival.
authors.affiliation: Department of Cell and Developmental Biology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Maryann
authors.initials: M
authors.lastname: Dassah
authors.forename: Dena
authors.initials: D
authors.lastname: Almeida
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hahn
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonaldo
authors.forename: Stefan
authors.initials: S
authors.lastname: Worgall
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hajjar
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000502:physiology*; D017209:Apoptosis; D001485:Basement Membrane; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D048430:Cell Shape; D002470:Cell Survival; D002478:Cells, Cultured; D024142:Collagen Type VI / Q000235:genetics / Q000378:metabolism*; D004548:Elasticity; D004847:Epithelial Cells / Q000378:metabolism* / Q000502:physiology; D017079:Exercise Tolerance; D006056:Golgi Apparatus / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D005082:Physical Exertion; D021381:Protein Transport; D012123:Pulmonary Ventilation; D020545:Respiratory Mucosa / Q000473:pathology; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism
chemical_list: D017306:Annexin A2; C540085:Col6a1 protein, mouse; D024142:Collagen Type VI; D050988:Vesicle-Associated Membrane Protein 2; C494808:vesicle-associated membrane protein 2, mouse
keywords: Annexin A2; Collagen VI; Secretion