AP-3-dependent targeting of flippase ATP8A1 to lamellar bodies suppresses activation of YAP in alveolar epithelial type 2 cells

Proc Natl Acad Sci U S A. 2021 May 18;118(20):e2025208118. doi: 10.1073/pnas.2025208118.

Abstract

Lamellar bodies (LBs) are lysosome-related organelles (LROs) of surfactant-producing alveolar type 2 (AT2) cells of the distal lung epithelium. Trafficking pathways to LBs have been understudied but are likely critical to AT2 cell homeostasis given associations between genetic defects of endosome to LRO trafficking and pulmonary fibrosis in Hermansky Pudlak syndrome (HPS). Our prior studies uncovered a role for AP-3, defective in HPS type 2, in trafficking Peroxiredoxin-6 to LBs. We now show that the P4-type ATPase ATP8A1 is sorted by AP-3 from early endosomes to LBs through recognition of a C-terminal dileucine-based signal. Disruption of the AP-3/ATP8A1 interaction causes ATP8A1 accumulation in early sorting and/or recycling endosomes, enhancing phosphatidylserine exposure on the cytosolic leaflet. This in turn promotes activation of Yes-activating protein, a transcriptional coactivator, augmenting cell migration and AT2 cell numbers. Together, these studies illuminate a mechanism whereby loss of AP-3-mediated trafficking contributes to a toxic gain-of-function that results in enhanced and sustained activation of a repair pathway associated with pulmonary fibrosis.

Keywords: endosome; lung epithelium; lysosome; pulmonary fibrosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Protein Complex 3 / genetics*
  • Adaptor Protein Complex 3 / metabolism
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adenosine Triphosphatases / genetics*
  • Adenosine Triphosphatases / metabolism
  • Alveolar Epithelial Cells / cytology
  • Alveolar Epithelial Cells / metabolism*
  • Animals
  • Biological Transport
  • Cell Line
  • Cell Movement
  • Disease Models, Animal
  • Endosomes / metabolism
  • Female
  • Gene Expression Regulation
  • Hermanski-Pudlak Syndrome / genetics*
  • Hermanski-Pudlak Syndrome / metabolism
  • Hermanski-Pudlak Syndrome / pathology
  • Humans
  • Lung / metabolism
  • Lung / pathology
  • Lysosomes / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Peroxiredoxin VI / genetics
  • Peroxiredoxin VI / metabolism
  • Phosphatidylserines / metabolism
  • Phospholipid Transfer Proteins / genetics*
  • Phospholipid Transfer Proteins / metabolism
  • Primary Cell Culture
  • Pulmonary Fibrosis / genetics*
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / pathology
  • Signal Transduction
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • YAP-Signaling Proteins
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism

Substances

  • Adaptor Protein Complex 3
  • Adaptor Proteins, Signal Transducing
  • Phosphatidylserines
  • Phospholipid Transfer Proteins
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Peroxiredoxin VI
  • ATP8A1 protein, human
  • Adenosine Triphosphatases
  • rab11 protein
  • rab GTP-Binding Proteins

Supplementary concepts

  • Hermansky Pudlak syndrome 2