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

Am J Physiol Lung Cell Mol Physiol. 2016 Mar 15;310(6):L519-31. doi: 10.1152/ajplung.00213.2015. Epub 2015 Dec 30.


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.

Keywords: Hermansky-Pudlak syndrome; Hermansky-Pudlak syndrome-associated interstitial pneumonia; alveolar epithelial cells; apoptosis; autophagy; lung fibrosis.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Epithelial Cells / physiology*
  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy*
  • Cell Line, Tumor
  • Female
  • Hermanski-Pudlak Syndrome / metabolism*
  • Hermanski-Pudlak Syndrome / pathology
  • Humans
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Membrane Proteins / genetics
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*


  • Apoptosis Regulatory Proteins
  • HPS1 protein, human
  • MAP1LC3B protein, human
  • Membrane Proteins
  • Microtubule-Associated Proteins