Presenilin Modulates Pen-2 Levels Posttranslationally by Protecting It from Proteasomal Degradation

Crystal, Adam S.; Fortna, Ryan R.; Carlin, Dan; Pierson, Theodore C.; Wilson, Christopher; Lee, Virginia M.‐Y.; Doms, Robert W.

doi:10.1021/bi0361214

Cited by 35 publications

(34 citation statements)

References 54 publications

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“…Altered Subcellular Localization of APH-1, PEN-2, and PS1 in the absence of Nct-Previous studies have established a role for PS1 in regulating trafficking of select membrane proteins including APP, PEN-2, and Nct (10,11,19,32,33,34). To investigate whether Nct may also be involved in subcellular localization of the other components, we examined the patterns of the ER and Golgi localization of PEN-2, APH-1, and PS1 in Nct KO and WT cells using a well established sucrose gradient fractionation method.…”

Section: Full-length Ps1 and Pen-2 Are Subjected To Proteasomemediatementioning

confidence: 99%

“…PS1 deficiency leads to a reduced level of PEN-2 (8, 9), which is due to ubiquitin-proteasome-mediated degradation (10,11). Recently, using biochemical approaches such as RNAi and protein overexpression, we and others (6,8) have demonstrated that PEN-2 is required for the endoproteolysis of PS1 and that APH-1 plays an important role in stabilizing PS1.…”

mentioning

confidence: 99%

“…Consistent with the localization of the active ␥-secretase complex, A␤ has been shown to be generated primarily in the Golgi/TGN (25)(26)(27), although other cellular compartments including ER (25,(27)(28)(29), endosomes (29,30), and plasma membrane (22,31) may also be involved. Recent studies from several groups including our own have demonstrated that, in the absence of PS1, Nct fails to be post-translationally glycosylated and the immature Nct and PEN-2 are sequestered in the ER and not transported to Golgi/TGN (10,11,19,32). These results suggest that, in addition to its critical role in the ␥-secretase activity, PS1 may regulate intracellular trafficking/maturation of other ␥-secretase components as well as the substrate APP (33,34).…”

mentioning

confidence: 99%

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Nicastrin Is Critical for Stability and Trafficking but Not Association of Other Presenilin/γ-Secretase Components

Zhang

Luo

Wang

et al. 2005

Journal of Biological Chemistry

106

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␥-Secretase, which is responsible for the intramembranous cleavage of Alzheimer ␤-amyloid precursor protein and the signaling receptor Notch, is a multiprotein complex consisting of at least four components: presenilin (PS); nicastrin (Nct); APH-1 (anterior pharynx-defective-1); and presenilin enhancer-2 (PEN-2). Presenilin 1 (PS1) is known to be essential for the stability, interaction, and trafficking of the other PS1/␥-secretase components. However, the precise functions of the other components remain elusive. Here, we investigated the functions of Nct within the PS1/␥-secretase complex. We demonstrated that the loss of Nct expression in the embryonic fibroblast cells (Nct KO cells) results in dramatically decreased levels of APH-1, PEN-2, and PS1 fragments accompanied by a significant accumulation of full-length PS1. In the absence of Nct, PEN-2 and fulllength PS1 are subjected to proteasome-mediated degradation, whereas the degradation of APH-1 is mediated by both proteasomal and lysosomal pathways. Unlike the case of wild type cells in which the ␥-secretase complex mainly locates in the trans-Golgi network, the majority of residual PEN-2, APH-1, and the uncleaved fulllength PS1 in Nct KO cells reside in the endoplasmic reticulum, which remain associated with each other in the absence of Nct. Interestingly, significant amounts of full-length PS1 and PEN-2, but not APH-1, are detected on the plasma membrane in Nct KO cells, suggesting the Nct-independent cell surface delivery of the PEN-2⅐PS1. Finally, the diminished PEN-2 protein level in Nct-deficient cells can be partially restored by overexpression of exogenous PS1, APH-1, or PEN-2 individually or collectively, indicating a dispensable role for Nct in controlling PEN-2 level. Taken together, our study demonstrates a critical role of Nct in the stability and proper intracellular trafficking of other components of the PS1/ ␥-secretase complex but not in maintaining the association of PEN-2, APH-1, and full-length PS1.

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Section: Full-length Ps1 and Pen-2 Are Subjected To Proteasomemediatementioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Nicastrin Is Critical for Stability and Trafficking but Not Association of Other Presenilin/γ-Secretase Components

Zhang

Luo

Wang

et al. 2005

Journal of Biological Chemistry

106

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“…The components of the ␥-secretase complex act upon each other: PS-1 is required for maturation of Nicastrin (19) and affects the stability of Pen-2 by inhibiting the proteosomemediated degradation (20,21). In turn, Pen-2 coordinately regulates proteolytic processing of PS-1 with Aph-1 (22) and is required for stabilization of the PS NTF/CTF heterodimer within the ␥-secretase complex (23).…”

mentioning

confidence: 99%

Presenilin-1 D257A and D385A Mutants Fail to Cleave Notch in Their Endoproteolyzed Forms, but Only Presenilin-1 D385A Mutant Can Restore Its γ-Secretase Activity with the Compensatory Overexpression of Normal C-terminal Fragment

Kim¹,

Ki²,

Park

et al. 2005

Journal of Biological Chemistry

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The enzyme ␥-secretase is involved in the cleavage of several type I membrane proteins, such as Notch 1 and amyloid precursor protein. Presenilin-1 (PS-1) is one of the critical integral membrane protein components of the ␥-secretase complex and is processed endoproteolytically, generating N-and C-terminal fragments (NTF and CTF, respectively). PS-1 is also known to incorporate into a high molecular weight complex by binding to other ␥-secretase components such as Nicastrin, Aph-1, and Pen-2. Mutations on PS-1 can alter the effects of ␥-secretase on its many substrates to different extents. Here, we showed that PS-1 mutants have a different activity for Notch cleavage, which depended on the PS-1 mutation site. We demonstrated that defective PS-1 mutants located in CTF, i.e. D385A and C410Y, could restore their ␥-secretase activities with the compensatory overexpression of wild type CTF or of minimal deleted CTF (amino acids 349 -467). However, the defective PS-1 D257A mutant could not restore their ␥-secretase activities with the compensatory overexpression of wild type NTF. In comparison, both D257A NTF and D385A CTF could abolish the ␥-secretase activity of wild type and pathogenic PS-1 mutants. We also showed that PS-1 NTF but not CTF forms strong high molecular weight aggregates in SDS-PAGE. Taken together, results have shown that NTF and CTF integrate differently into high molecular weight aggregates and that PS-1 Asp-257 and Asp-385 have different accessibilities in their unendoproteolyzed conformation.

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“…Especially, in fibroblasts this regulation depends on the p53 tumor suppressor (14). Also, at the translational level, PS selectively enhances the stability of Pen-2 and protects it from proteosomal degradation (15). However, there are no studies on the overexpression of human Pen-2 (hPen-2) gene in transtransgenic (Tg) mice, despite the importance of this approach in investigating the function of Pen-2 and for the screening of AD therapeutic drugs.…”

Section: Introductionmentioning

confidence: 99%

Pen-2 overexpression induces Aβ-42 production, memory defect, motor activity enhancement and feeding behavior dysfunction in NSE/Pen-2 transgenic mice

Nam

Seo²,

Goo³

et al. 2011

Int J Mol Med

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Abstract. Pen-2 is a key regulator of the γ-secretase complex, which is involved in the production of the amyloid β (Aβ)-42 peptides, which ultimately lead to Alzheimer's disease (AD). While Pen-2 has been studied in vitro, Pen-2 function in vivo in the brains of transgenic (Tg) mice overexpressing human Pen-2 (hPen-2) protein has not been studied. This study aimed to determine whether Pen-2 overexpression could regulate the AD-like phenotypes in Tg mice. NSE/hPen-2 Tg mice were produced by the microinjection of the NSE/hPen-2 gene into the pronucleus of fertilized eggs. The expression of the hPen-2 gene under the control of the NSE promoter was successfully detected only in the brain and kidney tissue of NSE/hPen-2 Tg mice. Also, 12-month-old NSE/hPen-2 Tg mice displayed behavioral dysfunction in the water maze test, motor activity and feeding behavior dysfunction in food intake/water intake/ motor activity monitoring system. In addition, tissue samples displayed dense staining with antibody to the Aβ-42 peptide. Furthermore, NSE/hPen-2 Tg mice exhibiting feeding behavior dysfunction were significantly more apt to display symptoms related to diabetes and obesity. These results suggest that Pen-2 overexpression in NSE/hPen-2 Tg mice may induce all the AD-like phenotypes, including behavioral deficits, motor activity and feeding behavior dysfunction, Aβ-42 peptide deposition and chronic disease induction.

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Presenilin Modulates Pen-2 Levels Posttranslationally by Protecting It from Proteasomal Degradation

Cited by 35 publications

References 54 publications

Nicastrin Is Critical for Stability and Trafficking but Not Association of Other Presenilin/γ-Secretase Components

Nicastrin Is Critical for Stability and Trafficking but Not Association of Other Presenilin/γ-Secretase Components

Presenilin-1 D257A and D385A Mutants Fail to Cleave Notch in Their Endoproteolyzed Forms, but Only Presenilin-1 D385A Mutant Can Restore Its γ-Secretase Activity with the Compensatory Overexpression of Normal C-terminal Fragment

Pen-2 overexpression induces Aβ-42 production, memory defect, motor activity enhancement and feeding behavior dysfunction in NSE/Pen-2 transgenic mice

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