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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

          Journal
          Am J Physiol Lung Cell Mol Physiol
          Am. J. Physiol. Lung Cell Mol. Physiol
          ajplung
          ajplung
          AJPLUNG
          American Journal of Physiology - Lung Cellular and Molecular Physiology
          American Physiological Society (Bethesda, MD )
          1040-0605
          1522-1504
          30 December 2015
          15 March 2016
          : 310
          : 6
          : L519-L531
          Affiliations
          [1] 1Department of Internal Medicine, Justus-Liebig University, Giessen, Germany;
          [2] 2Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Centre for Lung Research (DZL), Giessen, Germany;
          [3] 3Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany;
          [4] 4Biomedical Research in End-Stage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany;
          [5] 5REBIRTH Cluster of Excellence, Hannover, Germany;
          [6] 6Department of Pediatrics, Justus-Liebig-University, Giessen, Germany;
          [7] 7Excellence Cluster Cardiopulmonary System (ECCPS), Giessen, Germany;
          [8] 8Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland;
          [9] 9Member European IPF Registry/Biobank; and
          [10] 10Lung Clinic Waldhof-Elgershausen, Greifenstein, Germany
          Author notes
          [*]

          A. Guenther and P. Mahavadi contributed equally to this work.

          Address for reprint requests and other correspondence: A. Guenther, Klinikstrasse 36, 35392, Giessen, Germany (e-mail: Andreas.Guenther@ 123456innere.med.uni-giessen.de ).
          Article
          PMC4888554 PMC4888554 4888554 L-00213-2015
          10.1152/ajplung.00213.2015
          4888554
          26719147
          d94c3f32-e580-424c-bf1f-86d39ece512e
          Copyright © 2016 the American Physiological Society
          History
          : 30 June 2015
          : 24 December 2015
          Funding
          Funded by: Excellence Cluster Cardio-Pulmonary System
          Funded by: Intramural Research Program of the National Human Genome Research Institute,NIH
          Categories
          Call for Papers
          Translational Research in Acute Lung Injury and Pulmonary Fibrosis

          autophagy,Hermansky-Pudlak syndrome,alveolar epithelial cells,Hermansky-Pudlak syndrome-associated interstitial pneumonia,apoptosis,lung fibrosis

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