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AP-3-dependent targeting of flippase ATP8A1 to lamellar bodies suppresses activation of YAP in alveolar epithelial type 2 cells
- Source :
- Proc Natl Acad Sci U S A
- Publication Year :
- 2021
-
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.
- Subjects :
- Male
Endosome
Adaptor Protein Complex 3
Pulmonary Fibrosis
Cell
Primary Cell Culture
Endosomes
Phosphatidylserines
Lamellar granule
Cell Line
Mice
Cell Movement
Lysosome
Pulmonary fibrosis
Organelle
medicine
Animals
Humans
Phospholipid Transfer Proteins
Lung
Adaptor Proteins, Signal Transducing
Adenosine Triphosphatases
Multidisciplinary
Chemistry
Cell migration
Biological Transport
YAP-Signaling Proteins
Flippase
respiratory system
Biological Sciences
medicine.disease
Cell biology
Mice, Inbred C57BL
Disease Models, Animal
medicine.anatomical_structure
Gene Expression Regulation
Hermanski-Pudlak Syndrome
rab GTP-Binding Proteins
Alveolar Epithelial Cells
Female
Lysosomes
Peroxiredoxin VI
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 10916490
- Volume :
- 118
- Issue :
- 20
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....c9343c1e9403e7d8dc8bff9e9549ee6d