GGA proteins regulate retrograde transport of BACE1 from endosomes to the trans-Golgi network

Wahle, Tina; Prager, Kai; Raffler, Nikolai; Haass, Christian; Famulok, Michael; Walter, Jochen

doi:10.1016/j.mcn.2005.03.014

Cited by 119 publications

(133 citation statements)

References 39 publications

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“…Indeed, it has already been demonstrated that BACE1 is targeted from the TGN directly to endosomes through selective interactions of this motif with the three GGA proteins (2,3). From there, BACE1 can recycle back or traffic to the cell surface.…”

Section: Discussionmentioning

confidence: 99%

“…The major determinant in BACE1 sorting to and from endosomes is a short acidic cluster-dileucine motif (DISLL) in its cytosolic tail domain. This motif specifically binds to Golgi-localized γ-ear containing ADP ribosylation factor-binding (GGA-1, GGA-2, and GGA-3) proteins via their Vps, Hrs, and STAM domains (2,3). GGAs are involved in the selective transport of proteins, including the mannose-6-phosphate receptor, between the TGN and the endosome and in delivering endosomal cargoes for lysosomal degradation (4).…”

mentioning

confidence: 99%

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ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1

Sannerud

Declerck²,

Perić³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

216

232

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Amyloid β (Aβ) peptides, the primary constituents of senile plaques and a hallmark in Alzheimer's disease pathology, are generated through the sequential cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. The early endosome is thought to represent a major compartment for APP processing; however, the mechanisms of how BACE1 encounters APP are largely unknown. In contrast to APP internalization, which is clathrin-dependent, we demonstrate that BACE1 is sorted to early endosomes via a route controlled by the small GTPase ADP ribosylation factor 6 (ARF6). Altering ARF6 levels or its activity affects endosomal sorting of BACE1, and consequently results in altered APP processing and Aβ production. Furthermore, sorting of newly internalized BACE1 from ARF6-positive towards RAB GTPase 5 (RAB5)-positive early endosomes depends on its carboxyterminal short acidic cluster-dileucine motif. This ARF6-mediated sorting of BACE1 is confined to the somatodendritic compartment of polarized neurons in agreement with Aβ peptides being primarily secreted from here. These results demonstrate a spatial separation between APP and BACE1 during surface-toendosome transport, suggesting subcellular trafficking as a regulatory mechanism for this proteolytic processing step. It thereby provides a novel avenue to interfere with Aβ production through a selective modulation of the distinct endosomal transport routes used by BACE1 or APP.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1

Sannerud

Declerck²,

Perić³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

216

232

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“…A single phosphorylation at serine 498 within the carboxy-terminal domain of BACE1 is sufficient for its transport from endosomes to the trans-Golgi. Recycling requires the Golgilocalized, gamma-ear containing ADP (GGA) ribosylation-binding factor (He et al 2005;Wahle et al 2005Wahle et al , 2006, and two such GGA proteins are involved in BACE1 trafficking, GGA1 and GGA2. GGA1 is involved in endosomal retrieval of BACE1 and its recycling to the PM, whereas GGA2 targets BACE1 to lysosomes for its final degradation.…”

Section: Trafficking and Proteolytic Processing Of Appmentioning

confidence: 99%

Trafficking and Proteolytic Processing of APP

Haass¹,

Kaether²,

Wang³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

893

892

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Accumulations of insoluble deposits of amyloid b-peptide are major pathological hallmarks of Alzheimer disease. Amyloid b-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the b-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. b-and g-secretase liberate by sequential cleavage the neurotoxic amyloid b-peptide, whereas a-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid b-peptide generation and therefore disease onset and progression.

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“…Recently, it has been shown that GGA3 can bind BACE1 via the ubiquitin sorting machinery and regulate BACE1 degradation (16). It is well documented that GGAs mediate anterograde trafficking from the TGN to endosomes, but recent studies have suggested that GGAs might also act in retrograde trafficking of proteins, specifically of BACE1 (15,17). Furthermore, GGAs have recently been implicated in APP processing (18 -20).…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

BACE1 Retrograde Trafficking Is Uniquely Regulated by the Cytoplasmic Domain of Sortilin

Finan

Okada

Kim

2011

Journal of Biological Chemistry

103

107

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BACE1 (␤-site ␤-amyloid precursor protein (APP)-cleaving enzyme 1) mediates the first proteolytic cleavage of APP, leading to amyloid ␤-peptide (A␤) production. It has been reported that BACE1 intracellular trafficking, in particular endosometo-TGN sorting, is mediated by adaptor complexes, such as retromer and Golgi-localized ␥-ear-containing ARF-binding proteins (GGAs). Here we investigated whether sortilin, a Vps10p domain-sorting receptor believed to participate in retromer-mediated transport of select membrane cargoes, contributes to the subcellular trafficking and activity of BACE1. Our initial studies revealed increased levels of sortilin in post-mortem brain tissue of AD patients and that overexpression of sortilin leads to increased BACE1-mediated cleavage of APP in cultured cells. In contrast, RNAi suppression of sortilin results in decreased BACE1-mediated cleavage of APP. We also found that sortilin interacts with BACE1 and that a sortilin construct lacking its cytoplasmic domain, which contains putative retromer sorting motifs, remains bound to BACE1. However, expression of this truncated sortilin redistributes BACE1 from the trans-Golgi network to the endosomes and substantially reduces the retrograde trafficking of BACE1. Site-directed mutagenesis and chimera experiments reveal that the cytoplasmic tail of sortilin, but not those from other VPS10p domain receptors (e.g. SorCs1b and SorLA), plays a unique role in BACE1 trafficking. Our studies suggest a new function for sortilin as a modulator of BACE1 retrograde trafficking and subsequent generation of A␤.

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GGA proteins regulate retrograde transport of BACE1 from endosomes to the trans-Golgi network

Cited by 119 publications

References 39 publications

ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1

ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1

Trafficking and Proteolytic Processing of APP

BACE1 Retrograde Trafficking Is Uniquely Regulated by the Cytoplasmic Domain of Sortilin

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