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PMID: 17959829 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Mint3/X11gamma is an ADP-ribosylation factor-dependent adaptor that regulates the traffic of the Alzheimer's Precursor protein from the trans-Golgi network.

Molecular biology of the cell ·Vol. 19 ·No. 1 ·2008-01-00 ·Pages 51-64

Shrivastava-Ranjan P, Faundez V, Fang G, Rees H, Lah JJ, Levey AI, Kahn RA

Abstract

Beta-amyloid peptides (Abeta) are the major component of plaques in brains of Alzheimer's patients, and are they derived from the proteolytic processing of the beta-amyloid precursor protein (APP). The movement of APP between organelles is highly regulated, and it is tightly connected to its processing by secretases. We proposed previously that transport of APP within the cell is mediated in part through its sorting into Mint/X11-containing carriers. To test our hypothesis, we purified APP-containing vesicles from human neuroblastoma SH-SY5Y cells, and we showed that Mint2/3 are specifically enriched and that Mint3 and APP are present in the same vesicles. Increasing cellular APP levels increased the amounts of both APP and Mint3 in purified vesicles. Additional evidence supporting an obligate role for Mint3 in traffic of APP from the trans-Golgi network to the plasma membrane include the observations that depletion of Mint3 by small interference RNA (siRNA) or mutation of the Mint binding domain of APP changes the export route of APP from the basolateral to the endosomal/lysosomal sorting route. Finally, we show that increased expression of Mint3 decreased and siRNA-mediated knockdowns increased the secretion of the neurotoxic beta-amyloid peptide, Abeta(1-40). Together, our data implicate Mint3 activity as a critical determinant of post-Golgi APP traffic.

MeSH Terms
ADP-Ribosylation Factors/metabolism Adaptor Proteins, Signal Transducing Adaptor Proteins, Vesicular Transport/metabolism Alzheimer Disease/metabolism Amyloid beta-Peptides/isolation & purification,metabolism Brain/metabolism Cadherins/isolation & purification Carrier Proteins/isolation & purification,metabolism Cell Line, Tumor Endosomes/metabolism Humans Mutation Nerve Tissue Proteins/isolation & purification Protein Processing, Post-Translational Protein Structure, Tertiary Protein Transport RNA, Small Interfering/metabolism Subcellular Fractions/metabolism Transport Vesicles/metabolism,ultrastructure trans-Golgi Network/metabolism
Chemicals
APBA2 protein, human APBA3 protein, human Adaptor Proteins, Signal Transducing Adaptor Proteins, Vesicular Transport Amyloid beta-Peptides Cadherins Carrier Proteins Nerve Tissue Proteins RNA, Small Interfering ADP-Ribosylation Factors
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Shrivastava-Ranjan Punya
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322-3050, USA.
Faundez Victor
Fang Guofu
Rees Howard
Lah James J
Levey Allan I
Kahn Richard A
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1939-4586
DOI
10.1091/mbc.e07-05-0465
Published
2008-01-00
Epub
2007-00-24
Pages
51-64
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC2174186
Subset
IM
Grants
NINDS NIH HHS · R56 NS042599 · United States
NIGMS NIH HHS · GM-077569 · United States
NINDS NIH HHS · R01 NS042599 · United States
NIGMS NIH HHS · GM-67226 · United States
NINDS NIH HHS · NS-42599 · United States
NIA NIH HHS · P50 AG025688 · United States
NIGMS NIH HHS · R01 GM067226 · United States
NIGMS NIH HHS · R01 GM077569 · United States
NIA NIH HHS · AG-025688 · United States
External Links
PubMed source DOI: 10.1091/mbc.e07-05-0465 PMC Full Text View journal details
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