A reversible form of lysine acetylation in the ER and Golgi lumen controls the molecular stabilization of BACE1

Costantini, Claudio; Ko, Mi Hee; Jonas, Mary Cabell; Puglielli, Luigi

doi:10.1042/bj20070040

Cited by 103 publications

(175 citation statements)

References 49 publications

(81 reference statements)

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“…For example, reversible acetylation in the luminal domain of BACE1 regulates its stability as well as exit from the ER (20,57). Moreover, phosphorylation regulates the fate of BACE1 endocytosed from the cell surface; whereas phosphorylated BACE1 is transported from the endosomes to the TGN, non-phosphorylated BACE1 is directly recycled to the cell surface (18,29).…”

Section: Bace1 Is S-palmitoylated At 4 Cysteine Residues-previ-mentioning

confidence: 99%

Alzheimer Disease Aβ Production in the Absence of S-Palmitoylation-dependent Targeting of BACE1 to Lipid Rafts

Vetrivel

Meckler

Chen

et al. 2009

Journal of Biological Chemistry

137

138

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Alzheimer disease ␤-amyloid (A␤) peptides are generated via sequential proteolysis of amyloid precursor protein (APP) by BACE1 and ␥-secretase. A subset of BACE1 localizes to cholesterol-rich membrane microdomains, termed lipid rafts. BACE1 processing in raft microdomains of cultured cells and neurons was characterized in previous studies by disrupting the integrity of lipid rafts by cholesterol depletion. These studies found either inhibition or elevation of A␤ production depending on the extent of cholesterol depletion, generating controversy. The intricate interplay between cholesterol levels, APP trafficking, and BACE1 processing is not clearly understood because cholesterol depletion has pleiotropic effects on Golgi morphology, vesicular trafficking, and membrane bulk fluidity. In this study, we used an alternate strategy to explore the function of BACE1 in membrane microdomains without altering the cellular cholesterol level. We demonstrate that BACE1 undergoes S-palmitoylation at four Cys residues at the junction of transmembrane and cytosolic domains, and Ala substitution at these four residues is sufficient to displace BACE1 from lipid rafts. Analysis of wild type and mutant BACE1 expressed in BACE1 null fibroblasts and neuroblastoma cells revealed that S-palmitoylation neither contributes to protein stability nor subcellular localization of BACE1. Surprisingly, non-raft localization of palmitoylation-deficient BACE1 did not have discernible influence on BACE1 processing of APP or secretion of A␤. These results indicate that post-translational S-palmitoylation of BACE1 is not required for APP processing, and that BACE1 can efficiently cleave APP in both raft and non-raft microdomains.

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Section: Bace1 Is S-palmitoylated At 4 Cysteine Residues-previ-mentioning

confidence: 99%

Alzheimer Disease Aβ Production in the Absence of S-Palmitoylation-dependent Targeting of BACE1 to Lipid Rafts

Vetrivel

Meckler

Chen

et al. 2009

Journal of Biological Chemistry

137

138

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“…BACE1 belongs to the pepsin family and has a close homolog BACE2 (7). BACE1 is synthesized as a proenzyme in the endoplasmic reticulum, where it is acetylated (9) and glycosylated (10). During Golgi transit, BACE1 becomes deacetylated and mature N-glycosylated.…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Inhibition of β-Secretase in Vivo via Antibody Binding to Unique Loops (D and F) of BACE1

Zhou

Chávez‐Gutiérrez

Bockstael

et al. 2011

Journal of Biological Chemistry

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␤-Secretase (BACE1) is an attractive drug target for Alzheimer disease. However, the design of clinical useful inhibitors targeting its active site has been extremely challenging. To identify alternative drug targeting sites we have generated a panel of BACE1 monoclonal antibodies (mAbs) that interfere with BACE1 activity in various assays and determined their binding epitopes. mAb 1A11 inhibited BACE1 in vitro using a large APP sequence based substrate (IC 50 ϳ0.76 nM), in primary neurons (EC 50 ϳ1.8 nM), and in mouse brain after stereotactic injection. Paradoxically, mAb 1A11 increased BACE1 activity in vitro when a short synthetic peptide was used as substrate, indicating that mAb 1A11 does not occupy the active-site. Epitope mapping revealed that mAb 1A11 binds to adjacent loops D and F, which together with nearby helix A, distinguishes BACE1 from other aspartyl proteases. Interestingly, mutagenesis of loop F and helix A decreased or increased BACE1 activity, identifying them as enzymatic regulatory elements and as potential alternative sites for inhibitor design. In contrast, mAb 5G7 was a potent BACE1 inhibitor in cell-free enzymatic assays (IC 50 ϳ0.47 nM) but displayed no inhibitory effect in primary neurons. Its epitope, a surface helix 299 -312, is inaccessible in membrane-anchored BACE1. Remarkably, mutagenesis of helix 299 -312 strongly reduced BACE1 ectodomain shedding, suggesting that this helix plays a role in BACE1 cellular biology. In conclusion, this study generated highly selective and potent BACE1 inhibitory mAbs, which recognize unique structural and functional elements in BACE1, and uncovered interesting alternative sites on BACE1 that could become targets for drug development.

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“…Our group has shown that the TrkA to p75 NTR switch that occurs downstream of IGF1-R is responsible for the molecular stabilization of BACE1 and the increased generation of Aβ that accompanies aging [6,7,8,32]. The strict requirement for p75 NTR is proved by the fact that animals expressing a truncated version of the receptor (p75 NTRExonIII−/− ; lacking the ligand binding domain) were able to activate neither ceramide nor Aβ generation [8].…”

Section: Discussionmentioning

confidence: 99%

“…The TrkA to p75 NTR switch is responsible for an age-dependent activation of neutral sphingomyelinase (nSMase), the enzyme that converts cell-surface sphingomyelin (SM) into the second messenger ceramide. Ceramide, in turn, is responsible for the molecular stabilization of the β-site APP cleaving enzyme (BACE1), and for the increased β cleavage of the Alzheimer's disease (AD) amyloid precursor protein (APP) that accompanies aging [6,7,8,32]. These results are particularly important because aging is the single most important risk-factor for late-onset AD, which represents the most common form of dementia in the world [15,39].…”

Section: Disclosure Statementmentioning

confidence: 99%

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Egr-1 and Hipk2 are required for the TrkA to p75NTR switch that occurs downstream of IGF1-R

Costantini

Scrable

et al. 2009

Neurobiology of Aging

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The aging program mediated by IGF1-R is responsible for a naturally occurring TrkA-to-p75 NTR switch that leads to activation of the second messenger ceramide and increased production of the Alzheimer's disease amyloid β-peptide. Biochemical and genetic approaches that target IGF1-R signaling, p75 NTR , or ceramide are able to block the above events. Here, we show that the transcription factors Egr-1 and Hipk2 are required elements for the TrkA-to-p75 NTR switch downstream of IGF1-R signaling. Specifically, Egr-1 is required for the upregulation of p75 NTR , whereas Hipk2 is required for the downregulation of TrkA. In fact, gene silencing of Egr-1 abolished the ability of IGF1 to upregulate p75 NTR , whereas similar approaches directed against Hipk2 blocked the downregulation of TrkA. In addition, IGF1 treatment favored binding of Egr-1 and Hipk2 to the promoter of p75 NTR and TrkA, respectively. Finally, the expression levels of both Egr-1 and Hipk2 are upregulated in an age-dependent fashion. Such an event is opposed by caloric restriction, a model of delayed aging, and favored by the p44 transgene in p44 +/+ animals, a model of accelerated aging.

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A reversible form of lysine acetylation in the ER and Golgi lumen controls the molecular stabilization of BACE1

Cited by 103 publications

References 49 publications

Alzheimer Disease Aβ Production in the Absence of S-Palmitoylation-dependent Targeting of BACE1 to Lipid Rafts

Alzheimer Disease Aβ Production in the Absence of S-Palmitoylation-dependent Targeting of BACE1 to Lipid Rafts

Inhibition of β-Secretase in Vivo via Antibody Binding to Unique Loops (D and F) of BACE1

Egr-1 and Hipk2 are required for the TrkA to p75NTR switch that occurs downstream of IGF1-R

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