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Publication
AP-3-dependent targeting of flippase ATP8A1 to lamellar bodies suppresses
activation of YAP in alveolar epithelial type 2 cells.
Authors Kook S, Wang P, Meng S, Jetter CS, Sucre JMS, Benjamin JT, Gokey JJ, Hanby HA,
Jaume A, Goetzl L, Marks MS, Guttentag SH
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal Proceedings of the National Academy of Sciences of the United States of America
Year 2021
Date Published 5/1/2021
Volume : Pages 118 : Not Specified
PubMed Reference 33990468
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.




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