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      MAP1LC3B overexpression protects against Hermansky-Pudlak syndrome type-1-induced defective autophagy in vitro.

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          Abstract

          Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder, and some patients with HPS develop pulmonary fibrosis, known as HPS-associated interstitial pneumonia (HPSIP). We have previously reported that HPSIP is associated with severe surfactant accumulation, lysosomal stress, and alveolar epithelial cell type II (AECII) apoptosis. Here, we hypothesized that defective autophagy might result in excessive lysosomal stress in HPSIP. Key autophagy proteins, including LC3B lipidation and p62, were increased in HPS1/2 mice lungs. Electron microscopy demonstrated a preferable binding of LC3B to the interior of lamellar bodies in the AECII of HPS1/2 mice, whereas in wild-type mice it was present on the limiting membrane in addition to the interior of the lamellar bodies. Similar observations were noted in human HPS1 lung sections. In vitro knockdown of HPS1 revealed increased LC3B lipidation and p62 accumulation, associated with an increase in proapoptotic caspases. Overexpression of LC3B decreased the HPS1 knockdown-induced p62 accumulation, whereas rapamycin treatment did not show the same effect. We conclude that loss of HPS1 protein results in impaired autophagy that is restored by exogenous LC3B and that defective autophagy might therefore play a critical role in the development and progression of HPSIP.

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          Author and article information

          Affiliations
          [1 ] Department of Internal Medicine, Justus-Liebig University, Giessen, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Centre for Lung Research (DZL), Giessen, Germany;
          [2 ] Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany; Biomedical Research in End-Stage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany; REBIRTH Cluster of Excellence, Hannover, Germany;
          [3 ] Department of Internal Medicine, Justus-Liebig University, Giessen, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Centre for Lung Research (DZL), Giessen, Germany; Department of Pediatrics, Justus-Liebig-University, Giessen, Germany;
          [4 ] Department of Internal Medicine, Justus-Liebig University, Giessen, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Centre for Lung Research (DZL), Giessen, Germany; Excellence Cluster Cardiopulmonary System (ECCPS), Giessen, Germany;
          [5 ] Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland;
          [6 ] Department of Internal Medicine, Justus-Liebig University, Giessen, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Centre for Lung Research (DZL), Giessen, Germany; Excellence Cluster Cardiopulmonary System (ECCPS), Giessen, Germany; Member European IPF Registry/Biobank; and.
          [7 ] Department of Internal Medicine, Justus-Liebig University, Giessen, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Centre for Lung Research (DZL), Giessen, Germany; Excellence Cluster Cardiopulmonary System (ECCPS), Giessen, Germany; Member European IPF Registry/Biobank; and Lung Clinic Waldhof-Elgershausen, Greifenstein, Germany Andreas.Guenther@innere.med.uni-giessen.de.
          Journal
          Am. J. Physiol. Lung Cell Mol. Physiol.
          American journal of physiology. Lung cellular and molecular physiology
          American Physiological Society
          1522-1504
          1040-0605
          Mar 15 2016
          : 310
          : 6
          ajplung.00213.2015
          10.1152/ajplung.00213.2015
          4888554
          26719147

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