Open AccessAssembly of γ-secretase occurs through stable dimers after exit from the endoplasmic reticulum
Author(s) -
Rosanne Wouters,
Christine Michiels,
Ragna Sannerud,
Bertrand Kleizen,
Katleen Dillen,
Wendy Vermeire,
Abril Escamilla-Ayala,
David Demedts,
Randy Schekman,
Wim Annaert
Publication year - 2021
Publication title -
the journal of cell biology/the journal of cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.414
H-Index - 380
eISSN - 1540-8140
pISSN - 0021-9525
DOI - 10.1083/jcb.201911104
Subject(s) - nicastrin , endoplasmic reticulum , presenilin , golgi apparatus , biology , copii , microbiology and biotechnology , protein subunit , copi , psen1 , biogenesis , cytoplasm , secretory pathway , biochemistry , alzheimer's disease , gene , disease , medicine , pathology
γ-Secretase affects many physiological processes through targeting >100 substrates; malfunctioning links γ-secretase to cancer and Alzheimer’s disease. The spatiotemporal regulation of its stoichiometric assembly remains unresolved. Fractionation, biochemical assays, and imaging support prior formation of stable dimers in the ER, which, after ER exit, assemble into full complexes. In vitro ER budding shows that none of the subunits is required for the exit of others. However, knockout of any subunit leads to the accumulation of incomplete subcomplexes in COPII vesicles. Mutating a DPE motif in presenilin 1 (PSEN1) abrogates ER exit of PSEN1 and PEN-2 but not nicastrin. We explain this by the preferential sorting of PSEN1 and nicastrin through Sec24A and Sec24C/D, respectively, arguing against full assembly before ER exit. Thus, dimeric subcomplexes aided by Sec24 paralog selectivity support a stepwise assembly of γ-secretase, controlling final levels in post-Golgi compartments.