In Vivo Cleavage of α2,6-Sialyltransferase by Alzheimer β-Secretase

Kitazume, Shinobu; Nakagawa, Kazuhiro; Oka, Ritsuko; Tachida, Yuriko; Ogawa, Kazuko; Luo, Yi; Citron, Martin; Shitara, Hiroshi; Taya, Choji; Yonekawa, Hiromichi; Paulson, James C.; Miyoshi, Eiji; Taniguchi, Naoyuki; Hashimoto, Yasuhiro

doi:10.1074/jbc.m409417200

Cited by 90 publications

(75 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our findings correlate well with previous studies, demonstrating the residue preference for subsites of BACE1 using combinatorial inhibitor libraries (14,24); that is, BACE1 preferentially recognizes bulky hydrophobic residues, such as leucine (for VGSC␤1, -2, and -4) or phenylalanine (for VGSC␤3) at the P 1 site. Indeed, as an additional group of BACE1 substrates, the processing site of each VGSC␤ subunit is also comparable with that of rat ␤-galactoside ␣2,6-sialyltransferase (ST6GalI) and P-selectin glycoprotein ligand-1, the two known BACE1 substrates that are also cleaved by BACE1 after leucine residue (8,9,25,26). Furthermore, it is also worth noting that other protease(s), such as BACE2 (27,28), may also process VGSC␤ at the same (or very close) site, because the lack of BACE1 in MEFs and mouse brain only led to the reduction of CTF␤ production (Figs.…”

Section: Discussionmentioning

confidence: 99%

β Subunits of Voltage-gated Sodium Channels Are Novel Substrates of β-Site Amyloid Precursor Protein-cleaving Enzyme (BACE1) and γ-Secretase

Wong¹,

Sakurai

Oyama³

et al. 2005

Journal of Biological Chemistry

279

285

View full text Add to dashboard Cite

Sequential processing of amyloid precursor protein (APP) by membrane-bound proteases, BACE1 and ␥-secretase, plays a crucial role in the pathogenesis of Alzheimer disease. Much has been discovered on the properties of these proteases; however, regulatory mechanisms of enzyme-substrate interaction in neurons and their involvement in pathological changes are still not fully understood. It is mainly because of the membrane-associated cleavage of these proteases and the lack of information on new substrates processed in a similar way to APP. Here, using RNA interference-mediated BACE1 knockdown, mouse embryonic fibroblasts that are deficient in either BACE1 or presenilins, and BACE1-deficient mouse brain, we show clear evidence that ␤ subunits of voltage-gated sodium channels are sequentially processed by BACE1 and ␥-secretase. These results may provide new insights into the underlying pathology of Alzheimer disease.Alzheimer disease is a progressive neurodegenerative disorder and the most common form of age-dependent dementia. The major pathological features of Alzheimer disease are senile plaques and neurofibrillary tangles, which are the deposits of amyloid ␤ peptide (A␤) 1 and hyperphosphorylated tau, respectively. It is widely accepted that the sequential processing of APP, a type I membrane protein, by ␤-and ␥-secretases in the brain is crucial for the accumulation of A␤ and disease pathogenesis (1, 2). Although ␤-site APP-cleaving enzyme (BACE1) has been identified to be the ␤-secretase (3-6), a growing body of evidence favors presenilins-1 and -2 as the catalytic core of ␥-secretase (7). Although the properties of both proteases as APP processing enzymes are relatively well established, the regulatory mechanisms of sequential cleavage by both proteases in neurons are not completely clear. This is partly because of the fact that APP and its family proteins are still the only substrates identified for both ␤-and ␥-secretases, although a number of integral membrane proteins have been reported to be processed either by BACE1 (8, 9) or ␥-secretase (10). Identifying new substrates for both ␤-and ␥-secretases in neurons would therefore be useful to further explore the precise mechanism by which BACE1 and ␥-secretase function in cohort.Recently, our laboratory has been focusing on examining the role of voltage-gated sodium channel (VGSC) ␤ in the pathogenesis of Huntington disease and the regulation of APP processing in lipid rafts.2,3 VGSC is a large, multimeric complex that consists of an ␣ subunit and one or more ␤ subunits. To date, nine functional ␣ subunits and four ␤ subunits have been identified (11,12). Although VGSC␤ subunits are not essential to the basic operation of sodium channels, they are considered to be important auxiliary subunits, because co-expression of ␤ subunits are required to reconstitute full properties of the native sodium channel and to modify channel properties and intracellular localization (11,13). In the course of analyzing the VGSC␤, we found that these subunits are preferentially a...

show abstract

Section: Discussionmentioning

confidence: 99%

β Subunits of Voltage-gated Sodium Channels Are Novel Substrates of β-Site Amyloid Precursor Protein-cleaving Enzyme (BACE1) and γ-Secretase

Wong¹,

Sakurai

Oyama³

et al. 2005

Journal of Biological Chemistry

279

285

View full text Add to dashboard Cite

show abstract

“…In addition to APP, a number of other putative BACE1 substrates have been identified, including neuregulin (NRG1; Lindholm et al, 2002;Wong et al, 2005), voltage-gated sodium channel (VGSC; Na v ) subunits Kim et al, 2007), lipoproteinlike receptor related protein (LRP; von Arnim et al, 2005), amyloid precursor-like proteins (APLP; Li and Sudhof, 2004;Pastorino et al, 2004), P-selectin glycoprotein ligand 1 (PSGL-1; Lichtenthaler et al, 2003) and beta-galactoside alpha 2,6-sialyltransferase (ST6Gal I; Kitazume et al, 2005). Importantly, many of these substrates may play a role in neuronal function (NRG1, VGSCβ subunits) and the cellular response to stress and/or injury, such as recovery from excitotoxicity (Aβ; Kamenetz et al, 2003), Aβ clearance (LRP; Hyman et al, 2000), synapse formation (APP, APLP1, APLP2; Herms et al, 2004;Wang et al, 2005) and immune functions (PSGL-1, ST6Gal I; Lichtenthaler et al, 2003;Kitazume et al, 2005).…”

Section: Cellular Changes Associated With Vascular Diseases Can Elevamentioning

confidence: 99%

“…Importantly, many of these substrates may play a role in neuronal function (NRG1, VGSCβ subunits) and the cellular response to stress and/or injury, such as recovery from excitotoxicity (Aβ; Kamenetz et al, 2003), Aβ clearance (LRP; Hyman et al, 2000), synapse formation (APP, APLP1, APLP2; Herms et al, 2004;Wang et al, 2005) and immune functions (PSGL-1, ST6Gal I; Lichtenthaler et al, 2003;Kitazume et al, 2005). We speculate that following acute stress/injury BACE1 levels are elevated in order to facilitate recovery, a process that requires the cleavage of specific BACE1 substrates.…”

Section: Cellular Changes Associated With Vascular Diseases Can Elevamentioning

confidence: 99%

Linking vascular disorders and Alzheimer's disease: Potential involvement of BACE1

Cole¹,

Vassar²

2009

Neurobiology of Aging

View full text Add to dashboard Cite

The etiology of Alzheimer's disease (AD) remains unknown. However, specific risk factors have been identified, and aging is the strongest AD risk factor. The majority of cardiovascular events occur in older people and a close relationship between vascular disorders and AD exists. Amyloid plaques, composed of the beta amyloid peptide (Aβ), are hallmark lesions in AD and evidence indicates that Aβ plays a central role in AD pathophysiology. The BACE1 enzyme is essential for Aβ generation, and BACE1 levels are elevated in AD brain. The cause(s) of this BACE1 elevation remains undetermined. Here we review the potential contribution of vascular disease to AD pathogenesis. We examine the putative vasoactive properties of Aβ and how the cellular changes associated with vascular disease may elevate BACE1 levels. Despite increasing evidence, the exact role(s) vascular disorders play in AD remains to be determined. However, given that vascular diseases can be addressed by lifestyle and pharmacologic interventions, the potential benefits of these therapies in delaying the clinical appearance and progression of AD may warrant investigation.

show abstract

“…The principal source of soluble ST6Gal-1 is the liver, where the ST6Gal-1 catalytic domain is liberated from its membrane anchor by the proteolytic action of BACE1 (11)(12)(13). There have been reports suggesting that the untethered ST6Gal-1 glycosylates a different subset of hepatic glycoproteins than the tethered form (14,15).…”

mentioning

confidence: 99%

Role for Hepatic and Circulatory ST6Gal-1 Sialyltransferase in Regulating Myelopoiesis

Jones

Nasirikenari

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Recent findings have established a role for the ST6Gal-1 sialyltransferase in modulating inflammatory cell production during Th1 and Th2 responses. ST6Gal-1 synthesizes the Sia(␣2,6) to Gal(␤1,4)GlcNAc linkage on glycoproteins on cell surfaces and in systemic circulation. Engagement of P1, one of six promoter/regulatory regions driving murine ST6Gal-1 gene expression, generates the ST6Gal-1 for myelopoietic regulation. P1 utilization, however, is restricted to the liver and silent in hematopoietic cells. We considered the possibility that myelopoiesis is responsive to the sialylation of liver-derived circulatory glycoproteins, such that reduced ␣2,6-sialylation results in elevated myelopoiesis. However, 2-dimensional differential in gel electrophoresis (2D-DIGE) analysis disclosed only minimal alterations in the sialylation of sera glycoproteins of ST6Gal-1-deficient mice when compared with wild-type controls, either at baseline or during an acute phase response when the demand for sialylation is greatest. Furthermore, sera from ST6Gal-1-deficient animals did not enhance myelopoietic activity in ex vivo colony formation assays. Whereas there was only minimal consequence to the ␣2,6-sialylation of circulatory glycoproteins, ablation of the P1 promoter did result in strikingly depressed levels of ST6Gal-1 released into systemic circulation. Therefore, we considered the alternative possibility that myelopoiesis may be regulated not by the hepatic sialyl glycoproteins, but by the ST6Gal-1 that was released directly into circulation. Supporting this, ex vivo colony formation was notably attenuated upon introduction of physiologic levels of ST6Gal-1 into the culture medium. Our data support the idea that circulatory ST6Gal-1, mostly of hepatic origin, limits myelopoiesis by a mechanism independent of hepatic sialylation of serum glycoproteins.␣2,6-Sialic acid modification is a common feature of glycoproteins in systemic circulation, particularly those glycoproteins originating from the liver. The ␣2,6 attachment of sialic acid to Gal(␤1,4)GlcNAc termini of glycoproteins is mediated by the sialyltransferase ST6Gal-1. Mutant mice unable to express ST6Gal-1 are essentially devoid of ␣2,6-sialyl modifications, as evidenced by the lack of binding to the Sambucus nigra lectin (SNA) 2 that specifically recognizes these structures (1). Hepatic expression of ST6Gal-1 is principally driven by P1 (2, 3), one of six independently operative promoter regions regulating transcription of the ST6Gal-1 gene (4). Another promoter, P3, is responsible for low-level ST6Gal-1 expression in the liver (5). Increased expression of liver ST6Gal-1, mediated by the P1 promoter, has long been recognized to be an integral part of the acute phase response (APR) (6 -8), and it was generally believed that elevation of ST6Gal-1 was necessary to address the increased demand for sialylation of the acute phase proteins. The Siat1⌬P1 mouse, with a specific inactivation of P1 without compromising ST6Gal-1 gene expression from the remaining promoters, was ...

show abstract

In Vivo Cleavage of α2,6-Sialyltransferase by Alzheimer β-Secretase

Cited by 90 publications

References 47 publications

β Subunits of Voltage-gated Sodium Channels Are Novel Substrates of β-Site Amyloid Precursor Protein-cleaving Enzyme (BACE1) and γ-Secretase

β Subunits of Voltage-gated Sodium Channels Are Novel Substrates of β-Site Amyloid Precursor Protein-cleaving Enzyme (BACE1) and γ-Secretase

Linking vascular disorders and Alzheimer's disease: Potential involvement of BACE1

Role for Hepatic and Circulatory ST6Gal-1 Sialyltransferase in Regulating Myelopoiesis

Contact Info

Product

Resources

About