gamma-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation - PubMed (original) (raw)
. 2003 Mar 15;116(Pt 6):1127-36.
doi: 10.1242/jcs.00292.
Affiliations
- PMID: 12584255
- DOI: 10.1242/jcs.00292
Free article
gamma-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation
An Herreman et al. J Cell Sci. 2003.
Free article
Abstract
Nicastrin and presenilin are two major components of the gamma-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 gamma-secretase activity. However, when complex glycosylation of nicastrin was inhibited using mannosidase I inhibitors, gamma-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 gamma-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'.
Similar articles
- Localization of presenilin-nicastrin complexes and gamma-secretase activity to the trans-Golgi network.
Siman R, Velji J. Siman R, et al. J Neurochem. 2003 Mar;84(5):1143-53. doi: 10.1046/j.1471-4159.2003.01616.x. J Neurochem. 2003. PMID: 12603837 - Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins.
Yang DS, Tandon A, Chen F, Yu G, Yu H, Arawaka S, Hasegawa H, Duthie M, Schmidt SD, Ramabhadran TV, Nixon RA, Mathews PM, Gandy SE, Mount HT, St George-Hyslop P, Fraser PE. Yang DS, et al. J Biol Chem. 2002 Aug 2;277(31):28135-42. doi: 10.1074/jbc.M110871200. Epub 2002 May 24. J Biol Chem. 2002. PMID: 12032140 - Aph-2/Nicastrin: an essential component of gamma-secretase and regulator of Notch signaling and Presenilin localization.
Kopan R, Goate A. Kopan R, et al. Neuron. 2002 Jan 31;33(3):321-4. doi: 10.1016/s0896-6273(02)00585-8. Neuron. 2002. PMID: 11832221 Review. - Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex.
De Strooper B. De Strooper B. Neuron. 2003 Apr 10;38(1):9-12. doi: 10.1016/s0896-6273(03)00205-8. Neuron. 2003. PMID: 12691659 Review.
Cited by
- Dysregulation of hypoxia-inducible factor by presenilin/γ-secretase loss-of-function mutations.
Kaufmann MR, Barth S, Konietzko U, Wu B, Egger S, Kunze R, Marti HH, Hick M, Müller U, Camenisch G, Wenger RH. Kaufmann MR, et al. J Neurosci. 2013 Jan 30;33(5):1915-26. doi: 10.1523/JNEUROSCI.3402-12.2013. J Neurosci. 2013. PMID: 23365231 Free PMC article. - Assembly, maturation, and trafficking of the gamma-secretase complex in Alzheimer's disease.
Dries DR, Yu G. Dries DR, et al. Curr Alzheimer Res. 2008 Apr;5(2):132-46. doi: 10.2174/156720508783954695. Curr Alzheimer Res. 2008. PMID: 18393798 Free PMC article. Review. - Processing of the synaptic cell adhesion molecule neurexin-3beta by Alzheimer disease alpha- and gamma-secretases.
Bot N, Schweizer C, Ben Halima S, Fraering PC. Bot N, et al. J Biol Chem. 2011 Jan 28;286(4):2762-73. doi: 10.1074/jbc.M110.142521. Epub 2010 Nov 17. J Biol Chem. 2011. PMID: 21084300 Free PMC article. - Mutant presenilin 1 increases the expression and activity of BACE1.
Giliberto L, Borghi R, Piccini A, Mangerini R, Sorbi S, Cirmena G, Garuti A, Ghetti B, Tagliavini F, Mughal MR, Mattson MP, Zhu X, Wang X, Guglielmotto M, Tamagno E, Tabaton M. Giliberto L, et al. J Biol Chem. 2009 Apr 3;284(14):9027-38. doi: 10.1074/jbc.M805685200. Epub 2009 Feb 5. J Biol Chem. 2009. PMID: 19196715 Free PMC article. - Mutations in nicastrin protein differentially affect amyloid beta-peptide production and Notch protein processing.
Pamrén A, Wanngren J, Tjernberg LO, Winblad B, Bhat R, Näslund J, Karlström H. Pamrén A, et al. J Biol Chem. 2011 Sep 9;286(36):31153-8. doi: 10.1074/jbc.C111.235267. Epub 2011 Jul 18. J Biol Chem. 2011. PMID: 21768095 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources