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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.

SUBMITTER: Dassah M

PROVIDER: S-EPMC3924203 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Annexin A2 mediates secretion of collagen VI, pulmonary elasticity and apoptosis of bronchial epithelial cells.

Dassah Maryann M Almeida Dena D Hahn Rebecca R Bonaldo Paolo P Worgall Stefan S Hajjar Katherine A KA

Journal of cell science 20131219 Pt 4

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 e ...[more]

PMID: 24357721

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Project description:The spectrum of clinical phenotypes associated with a deficiency or dysfunction of collagen VI in the extracellular matrix of muscle are collectively termed 'collagen VI-related myopathies' and include Ullrich congenital muscular dystrophy, Bethlem myopathy and intermediate phenotypes. To further define the clinical course of these variants, we studied the natural history of pulmonary function in correlation to motor abilities in the collagen VI-related myopathies by analysing longitudinal forced vital capacity data in a large international cohort. Retrospective chart reviews of genetically and/or pathologically confirmed collagen VI-related myopathy patients were performed at 10 neuromuscular centres: USA (n = 2), UK (n = 2), Australia (n = 2), Italy (n = 2), France (n = 1) and Belgium (n = 1). A total of 486 forced vital capacity measurements obtained in 145 patients were available for analysis. Patients at the severe end of the clinical spectrum, conforming to the original description of Ullrich congenital muscular dystrophy were easily identified by severe muscle weakness either preventing ambulation or resulting in an early loss of ambulation, and demonstrated a cumulative decline in forced vital capacity of 2.6% per year (P < 0.0001). Patients with better functional abilities, in whom walking with/without assistance was achieved, were initially combined, containing both intermediate and Bethlem myopathy phenotypes in one group. However, one subset of patients demonstrated a continuous decline in pulmonary function whereas the other had stable pulmonary function. None of the patients with declining pulmonary function attained the ability to hop or run; these patients were categorized as intermediate collagen VI-related myopathy and the remaining patients as Bethlem myopathy. Intermediate patients had a cumulative decline in forced vital capacity of 2.3% per year (P < 0.0001) whereas the relationship between age and forced vital capacity in patients with Bethlem myopathy was not significant (P = 0.1432). Nocturnal non-invasive ventilation was initiated in patients with Ullrich congenital muscular dystrophy by 11.3 years (±4.0) and in patients with intermediate collagen VI-related myopathy by 20.7 years (±1.5). The relationship between maximal motor ability and forced vital capacity was highly significant (P < 0.0001). This study demonstrates that pulmonary function profiles can be used in combination with motor function profiles to stratify collagen VI-related myopathy patients phenotypically. These findings improve our knowledge of the natural history of the collagen VI-related myopathies, enabling proactive optimization of care and preparing this patient population for clinical trials.

Dataset Information

Annexin A2 mediates secretion of collagen VI, pulmonary elasticity and apoptosis of bronchial epithelial cells.

Publications

Annexin A2 mediates secretion of collagen VI, pulmonary elasticity and apoptosis of bronchial epithelial cells.

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