γ-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation
10.1242/jcs.00292
Crossref journal-article
The Company of Biologists
Journal of Cell Science (237)
Abstract

Nicastrin and presenilin are two major components of the γ-secretase complex, which executes the intramembrane proteolysis of type I integral membrane proteins such as the amyloid precursor protein (APP) and Notch. Nicastrin is synthesized in fibroblasts and neurons as an endoglycosidase-H-sensitive glycosylated precursor protein (immature nicastrin) and is then modified by complex glycosylation in the Golgi apparatus and by sialylation in the trans-Golgi network (mature nicastrin). These modifications are not observed with exogenously overexpressed nicastrin. Under normal cell culture conditions, only mature nicastrin is expressed at the cell surface and binds to the presenilin heterodimers. Mature nicastrin has a half-life of more than 24 hours. In the absence of presenilin 1 and 2,nicastrin remains entirely endoglycosidase H sensitive, is retained in the endoplasmic reticulum and is slowly degraded. Single presenilin 1 or presenilin 2 deficiency affects glycosylation of nicastrin to a lesser extent than the combined presenilin deficiencies, suggesting a correlation between either the transport of nicastrin out of the endoplasmic reticulum or the concomitant complex glycosylation of nicastrin, and γ-secretase activity. However, when complex glycosylation of nicastrin was inhibited using mannosidase I inhibitors, γ-secretase cleavage of APP or Notch was not inhibited and the immature nicastrin still associates with presenilin and appears at the cell surface. Complex glycosylation of nicastrin is therefore not needed for γ-secretase activity. Because the trafficking of nicastrin to the Golgi apparatus is dependent on presenilins, our data point to a central role of presenilin in nicastrin maturation/localization, which could help to partially resolve the `spatial paradox'.

Bibliography

Herreman, A., Van Gassen, G., Bentahir, M., Nyabi, O., Craessaerts, K., Mueller, U., Annaert, W., & De Strooper, B. (2003). γ-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation. Journal of Cell Science, 116(6), 1127–1136.

Authors 8
  1. An Herreman (first)
  2. Geert Van Gassen (additional)
  3. Mustapha Bentahir (additional)
  4. Omar Nyabi (additional)
  5. Katleen Craessaerts (additional)
  6. Ulrike Mueller (additional)
  7. Wim Annaert (additional)
  8. Bart De Strooper (additional)
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Dates
Type When
Created 22 years, 6 months ago (Feb. 12, 2003, 8:49 p.m.)
Deposited 4 years, 4 months ago (April 25, 2021, 2:54 p.m.)
Indexed 2 days, 3 hours ago (Aug. 28, 2025, 8:33 a.m.)
Issued 22 years, 5 months ago (March 15, 2003)
Published 22 years, 5 months ago (March 15, 2003)
Published Print 22 years, 5 months ago (March 15, 2003)
Funders 0

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@article{Herreman_2003, title={γ-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation}, volume={116}, ISSN={0021-9533}, url={http://dx.doi.org/10.1242/jcs.00292}, DOI={10.1242/jcs.00292}, number={6}, journal={Journal of Cell Science}, publisher={The Company of Biologists}, author={Herreman, An and Van Gassen, Geert and Bentahir, Mustapha and Nyabi, Omar and Craessaerts, Katleen and Mueller, Ulrike and Annaert, Wim and De Strooper, Bart}, year={2003}, month=mar, pages={1127–1136} }