Spatial snapshots of amyloid precursor protein intramembrane processing via early endosome proteomics

Hankum Park, Frances V. Hundley, Qing Yu, Katherine A. Overmyer, Dain R. Brademan, Lia Serrano, Joao A. Paulo, Julia C. Paoli, Sharan Swarup, Joshua J. Coon, Steven P. Gygi and J. Wade Harper ()
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Hankum Park: Harvard Medical School
Frances V. Hundley: Harvard Medical School
Qing Yu: Harvard Medical School
Katherine A. Overmyer: University of Wisconsin–Madison
Dain R. Brademan: University of Wisconsin–Madison
Lia Serrano: University of Wisconsin–Madison
Joao A. Paulo: Harvard Medical School
Julia C. Paoli: Harvard Medical School
Sharan Swarup: Harvard Medical School
Joshua J. Coon: University of Wisconsin–Madison
Steven P. Gygi: Harvard Medical School
J. Wade Harper: Harvard Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: Abstract Degradation and recycling of plasma membrane proteins occurs via the endolysosomal system, wherein endosomes bud into the cytosol from the plasma membrane and subsequently mature into degradative lysosomal compartments. While methods have been developed for rapid selective capture of lysosomes (Lyso-IP), analogous methods for isolation of early endosome intermediates are lacking. Here, we develop an approach for rapid isolation of early/sorting endosomes through affinity capture of the early endosome-associated protein EEA1 (Endo-IP) and provide proteomic and lipidomic snapshots of EEA1-positive endosomes in action. We identify recycling, regulatory and membrane fusion complexes, as well as candidate cargo, providing a proteomic landscape of early/sorting endosomes. To demonstrate the utility of the method, we combined Endo- and Lyso-IP with multiplexed targeted proteomics to provide a spatial digital snapshot of amyloid precursor protein (APP) processing by β and γ-Secretases, which produce amyloidogenic Aβ species, and quantify small molecule modulation of Secretase action on endosomes. We anticipate that the Endo-IP approach will facilitate systematic interrogation of processes that are coordinated on EEA1-positive endosomes.

Date: 2022
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DOI: 10.1038/s41467-022-33881-x

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