Cargando…
Cysteine-rich domain of scavenger receptor AI modulates the efficacy of surface targeting and mediates oligomeric Aβ internalization
BACKGROUND: Insufficient clearance of soluble oligomeric amyloid-β peptide (oAβ) in the central nervous system leads to the synaptic and memory deficits in Alzheimer's disease (AD). Previously we have identified scavenger receptor class A (SR-A) of microglia mediates oligomeric amyloid-β peptid...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750411/ https://www.ncbi.nlm.nih.gov/pubmed/23915271 http://dx.doi.org/10.1186/1423-0127-20-54 |
_version_ | 1782477119730745344 |
---|---|
author | Huang, Fong-Lee Shiao, Young-Ji Hou, Sheue-Jane Yang, Cheng-Ning Chen, Yi-Jen Lin, Chao-Hsiung Shie, Feng-Shiun Tsay, Huey-Jen |
author_facet | Huang, Fong-Lee Shiao, Young-Ji Hou, Sheue-Jane Yang, Cheng-Ning Chen, Yi-Jen Lin, Chao-Hsiung Shie, Feng-Shiun Tsay, Huey-Jen |
author_sort | Huang, Fong-Lee |
collection | PubMed |
description | BACKGROUND: Insufficient clearance of soluble oligomeric amyloid-β peptide (oAβ) in the central nervous system leads to the synaptic and memory deficits in Alzheimer's disease (AD). Previously we have identified scavenger receptor class A (SR-A) of microglia mediates oligomeric amyloid-β peptide (oAβ) internalization by siRNA approach. SR-A is a member of cysteine-rich domain (SRCR) superfamily which contains proteins actively modulating the innate immunity and host defense, however the functions of the SRCR domain remain unclear. Whether the SRCR domain of SR-AI modulates the receptor surface targeting and ligand internalization was investigated by expressing truncated SR-A variants in COS-7 cells. Surface targeting of SR-A variants was examined by live immunostaining and surface biotinylation assays. Transfected COS-7 cells were incubated with fluorescent oAβ and acetylated LDL (AcLDL) to assess their ligand-internalization capabilities. RESULT: Genetic ablation of SR-A attenuated the internalization of oAβ and AcLDL by microglia. Half of oAβ-containing endocytic vesicles was SR-A positive in both microglia and macrophages. Clathrin and dynamin in SR-AI-mediated oAβ internalization were involved. The SRCR domain of SR-AI is encoded by exons 10 and 11. SR-A variants with truncated exon 11 were intracellularly retained, whereas SR-A variants with further truncations into exon 10 were surface-targeted. The fusion of exon 11 to the surface-targeted SR-A variant lacking the SRCR domain resulted in the intracellular retention and the co-immunoprecipitation of Bip chaperon of the endoplasmic reticulum. Surface-targeted variants were N-glycosylated, whereas intracellularly-retained variants retained in high-mannose states. In addition to the collagenous domain, the SRCR domain is a functional binding domain for oAβ and AcLDL. Our data suggest that inefficient folding of SR-AI variants with truncated SRCR domain was recognized by the endoplasmic reticulum associated degradation which leads to the immature N- glycosylation and intracellular retention. CONCLUSION: The novel functions of the SRCR domain on regulating the efficacy of receptor trafficking and ligand binding may lead to possible approaches on modulating the innate immunity in Alzheimer’s disease and atherosclerosis. |
format | Online Article Text |
id | pubmed-3750411 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-37504112013-08-24 Cysteine-rich domain of scavenger receptor AI modulates the efficacy of surface targeting and mediates oligomeric Aβ internalization Huang, Fong-Lee Shiao, Young-Ji Hou, Sheue-Jane Yang, Cheng-Ning Chen, Yi-Jen Lin, Chao-Hsiung Shie, Feng-Shiun Tsay, Huey-Jen J Biomed Sci Research BACKGROUND: Insufficient clearance of soluble oligomeric amyloid-β peptide (oAβ) in the central nervous system leads to the synaptic and memory deficits in Alzheimer's disease (AD). Previously we have identified scavenger receptor class A (SR-A) of microglia mediates oligomeric amyloid-β peptide (oAβ) internalization by siRNA approach. SR-A is a member of cysteine-rich domain (SRCR) superfamily which contains proteins actively modulating the innate immunity and host defense, however the functions of the SRCR domain remain unclear. Whether the SRCR domain of SR-AI modulates the receptor surface targeting and ligand internalization was investigated by expressing truncated SR-A variants in COS-7 cells. Surface targeting of SR-A variants was examined by live immunostaining and surface biotinylation assays. Transfected COS-7 cells were incubated with fluorescent oAβ and acetylated LDL (AcLDL) to assess their ligand-internalization capabilities. RESULT: Genetic ablation of SR-A attenuated the internalization of oAβ and AcLDL by microglia. Half of oAβ-containing endocytic vesicles was SR-A positive in both microglia and macrophages. Clathrin and dynamin in SR-AI-mediated oAβ internalization were involved. The SRCR domain of SR-AI is encoded by exons 10 and 11. SR-A variants with truncated exon 11 were intracellularly retained, whereas SR-A variants with further truncations into exon 10 were surface-targeted. The fusion of exon 11 to the surface-targeted SR-A variant lacking the SRCR domain resulted in the intracellular retention and the co-immunoprecipitation of Bip chaperon of the endoplasmic reticulum. Surface-targeted variants were N-glycosylated, whereas intracellularly-retained variants retained in high-mannose states. In addition to the collagenous domain, the SRCR domain is a functional binding domain for oAβ and AcLDL. Our data suggest that inefficient folding of SR-AI variants with truncated SRCR domain was recognized by the endoplasmic reticulum associated degradation which leads to the immature N- glycosylation and intracellular retention. CONCLUSION: The novel functions of the SRCR domain on regulating the efficacy of receptor trafficking and ligand binding may lead to possible approaches on modulating the innate immunity in Alzheimer’s disease and atherosclerosis. BioMed Central 2013-08-02 /pmc/articles/PMC3750411/ /pubmed/23915271 http://dx.doi.org/10.1186/1423-0127-20-54 Text en Copyright © 2013 Huang et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Huang, Fong-Lee Shiao, Young-Ji Hou, Sheue-Jane Yang, Cheng-Ning Chen, Yi-Jen Lin, Chao-Hsiung Shie, Feng-Shiun Tsay, Huey-Jen Cysteine-rich domain of scavenger receptor AI modulates the efficacy of surface targeting and mediates oligomeric Aβ internalization |
title | Cysteine-rich domain of scavenger receptor AI modulates the efficacy of surface targeting and mediates oligomeric Aβ internalization |
title_full | Cysteine-rich domain of scavenger receptor AI modulates the efficacy of surface targeting and mediates oligomeric Aβ internalization |
title_fullStr | Cysteine-rich domain of scavenger receptor AI modulates the efficacy of surface targeting and mediates oligomeric Aβ internalization |
title_full_unstemmed | Cysteine-rich domain of scavenger receptor AI modulates the efficacy of surface targeting and mediates oligomeric Aβ internalization |
title_short | Cysteine-rich domain of scavenger receptor AI modulates the efficacy of surface targeting and mediates oligomeric Aβ internalization |
title_sort | cysteine-rich domain of scavenger receptor ai modulates the efficacy of surface targeting and mediates oligomeric aβ internalization |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750411/ https://www.ncbi.nlm.nih.gov/pubmed/23915271 http://dx.doi.org/10.1186/1423-0127-20-54 |
work_keys_str_mv | AT huangfonglee cysteinerichdomainofscavengerreceptoraimodulatestheefficacyofsurfacetargetingandmediatesoligomericabinternalization AT shiaoyoungji cysteinerichdomainofscavengerreceptoraimodulatestheefficacyofsurfacetargetingandmediatesoligomericabinternalization AT housheuejane cysteinerichdomainofscavengerreceptoraimodulatestheefficacyofsurfacetargetingandmediatesoligomericabinternalization AT yangchengning cysteinerichdomainofscavengerreceptoraimodulatestheefficacyofsurfacetargetingandmediatesoligomericabinternalization AT chenyijen cysteinerichdomainofscavengerreceptoraimodulatestheefficacyofsurfacetargetingandmediatesoligomericabinternalization AT linchaohsiung cysteinerichdomainofscavengerreceptoraimodulatestheefficacyofsurfacetargetingandmediatesoligomericabinternalization AT shiefengshiun cysteinerichdomainofscavengerreceptoraimodulatestheefficacyofsurfacetargetingandmediatesoligomericabinternalization AT tsayhueyjen cysteinerichdomainofscavengerreceptoraimodulatestheefficacyofsurfacetargetingandmediatesoligomericabinternalization |