Cysteine-rich domain of scavenger receptor AI modulates the efficacy of surface targeting and mediates oligomeric Aβ internalization

Journal of Biomedical Science

Huey-Jen Tsay⁴  Feng-Shiun Shie¹  Chao-Hsiung Lin²  Yi-Jen Chen⁴  Cheng-Ning Yang⁴  Sheue-Jane Hou⁶  Young-Ji Shiao³  Fong-Lee Huang⁵ 

[1] Division of Mental Health and Addiction Medicine, the Institute of Population Health Sciences, National Health Research Institutes, No. 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan;Department of Life Sciences, Institute of Genome Sciences National Yang-Ming University, Taipei 11221, Taiwan;National Research Institute of Chinese Medicines, Taipei 11221, Taiwan;Institute of Neuroscience, Brain Research Center, School of Life Science, National Yang-Ming University, 155, Li-Nung Street, Section 2, Taipei 11221, Taiwan;Institute of Anatomy and Cell Biology, National Yang-Ming University, Taipei 11221, Taiwan;Department of Psychiatry, Cheng Hsin General Hospital, Taipei 112, Taiwan

关键词: N- glycosylation;    Amyloid-β peptide;    Collagenous domain;    SRCR domain;    Scavenger receptor A;   

Others  :  823497
DOI  :  10.1186/1423-0127-20-54

 received in 2013-04-13, accepted in 2013-07-30,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Huang et al.; licensee BioMed Central Ltd.

【 图 表 】

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