APP/APLP2 expression is required to initiate endosome-nucleus-autophagosome trafficking of glypican-1-derived heparan sulfate.
Cheng, Fang LU ; Cappai, Roberto ; Lidfeldt, Jon LU
; Belting, Mattias
LU
; Fransson, Lars-Åke
LU
and Mani, Katrin
LU
(2014)
In Journal of Biological Chemistry
289(30).
p.20871-20878
- Abstract
- Anhydromannose (anMan)-containing heparan sulfate (HS) derived from the proteoglycan glypican-1 (Gpc-1) is generated in endosomes by an endogenously or ascorbate induced SNO-catalyzed reaction. Processing of the amyloid precursor protein (APP) and APP-like protein 2 (APLP2) by β- and γ-secretases into amyloid beta (Aβ) and Aβ-like peptides also takes place in these compartments. Moreover, anMan-containing HS suppresses the formation of toxic Aβ assemblies in vitro. We show by using deconvolution immunofluorescence microscopy with an anMan-specific monoclonal antibody as well as 35S-labeling experiment that expression of APP/APLP2 is required for ascorbate-induced transport of HS from endosomes to the nucleus. Nuclear translocation was... (More)
- Anhydromannose (anMan)-containing heparan sulfate (HS) derived from the proteoglycan glypican-1 (Gpc-1) is generated in endosomes by an endogenously or ascorbate induced SNO-catalyzed reaction. Processing of the amyloid precursor protein (APP) and APP-like protein 2 (APLP2) by β- and γ-secretases into amyloid beta (Aβ) and Aβ-like peptides also takes place in these compartments. Moreover, anMan-containing HS suppresses the formation of toxic Aβ assemblies in vitro. We show by using deconvolution immunofluorescence microscopy with an anMan-specific monoclonal antibody as well as 35S-labeling experiment that expression of APP/APLP2 is required for ascorbate-induced transport of HS from endosomes to the nucleus. Nuclear translocation was observed in wild-type mouse embryonic fibroblasts (Wt-MEF), Tg2576 MEF and N2a neuroblastoma cells but not in APP-/- and APLP2-/- MEF. Transfection of APP-/- cells with a vector encoding APP restored nuclear import of anMan-containing HS. In Wt-MEF and N2a neuroblastoma cells exposed to β- or γ-secretase inhibitors, nuclear translocation was greatly impeded, suggesting involvement of APP/APLP2 degradation products. In Tg2576 MEF, the β-inhibitor blocked transport but the γ- inhibitor did not. During chase in ascorbate-free medium, anMan-containing HS disappeared from the nuclei of Wt-MEF. Confocal immunofluorescence microscopy showed that they appeared in acidic, LC3-positive vesicles in keeping with an autophagosomal location. There was increased accumulation of anMan-containing HS in nuclei and cytosolic vesicles upon treatment with chloroquine indicating that HS was degraded in lysosomes. Manipulations of APP expression and processing may have deleterious effects upon HS function in the nucleus. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4529242
- author
- Cheng, Fang
LU
; Cappai, Roberto
; Lidfeldt, Jon
LU
; Belting, Mattias
LU
; Fransson, Lars-Åke
LU
and Mani, Katrin
LU
- organization
- publishing date
- 2014
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 289
- issue
- 30
- pages
- 20871 - 20878
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- pmid:24898256
- wos:000339396600041
- scopus:84905373399
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.M114.552810
- language
- English
- LU publication?
- yes
- id
- 5e9f034a-cec7-49bd-bc80-9c4bd74bb2bb (old id 4529242)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/24898256?dopt=Abstract
- date added to LUP
- 2016-04-01 10:48:06
- date last changed
- 2023-09-28 14:15:41
@article{5e9f034a-cec7-49bd-bc80-9c4bd74bb2bb,
abstract = {{Anhydromannose (anMan)-containing heparan sulfate (HS) derived from the proteoglycan glypican-1 (Gpc-1) is generated in endosomes by an endogenously or ascorbate induced SNO-catalyzed reaction. Processing of the amyloid precursor protein (APP) and APP-like protein 2 (APLP2) by β- and γ-secretases into amyloid beta (Aβ) and Aβ-like peptides also takes place in these compartments. Moreover, anMan-containing HS suppresses the formation of toxic Aβ assemblies in vitro. We show by using deconvolution immunofluorescence microscopy with an anMan-specific monoclonal antibody as well as 35S-labeling experiment that expression of APP/APLP2 is required for ascorbate-induced transport of HS from endosomes to the nucleus. Nuclear translocation was observed in wild-type mouse embryonic fibroblasts (Wt-MEF), Tg2576 MEF and N2a neuroblastoma cells but not in APP-/- and APLP2-/- MEF. Transfection of APP-/- cells with a vector encoding APP restored nuclear import of anMan-containing HS. In Wt-MEF and N2a neuroblastoma cells exposed to β- or γ-secretase inhibitors, nuclear translocation was greatly impeded, suggesting involvement of APP/APLP2 degradation products. In Tg2576 MEF, the β-inhibitor blocked transport but the γ- inhibitor did not. During chase in ascorbate-free medium, anMan-containing HS disappeared from the nuclei of Wt-MEF. Confocal immunofluorescence microscopy showed that they appeared in acidic, LC3-positive vesicles in keeping with an autophagosomal location. There was increased accumulation of anMan-containing HS in nuclei and cytosolic vesicles upon treatment with chloroquine indicating that HS was degraded in lysosomes. Manipulations of APP expression and processing may have deleterious effects upon HS function in the nucleus.}},
author = {{Cheng, Fang and Cappai, Roberto and Lidfeldt, Jon and Belting, Mattias and Fransson, Lars-Åke and Mani, Katrin}},
issn = {{1083-351X}},
language = {{eng}},
number = {{30}},
pages = {{20871--20878}},
publisher = {{American Society for Biochemistry and Molecular Biology}},
series = {{Journal of Biological Chemistry}},
title = {{APP/APLP2 expression is required to initiate endosome-nucleus-autophagosome trafficking of glypican-1-derived heparan sulfate.}},
url = {{https://lup.lub.lu.se/search/files/2144241/5051211.pdf}},
doi = {{10.1074/jbc.M114.552810}},
volume = {{289}},
year = {{2014}},
}