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Structural requirements for multimerization of the pathogen receptor dendritic cell-specific ICAM3-grabbing
Diego Serrano-Gómez1, Elena Sierra-Filardi, Rocío T Martínez-Nuñez
1Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, Madrid 28040, Spain.
Insights
Dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN) neck variants affect cell surface multimerization and pathogen binding. These variations influence susceptibility to infections like HIV-1.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN, CD209) is a C-type lectin expressed on myeloid cells.
- DC-SIGN recognizes ligands on pathogens such as HIV, Mycobacterium, and Aspergillus.
- Alternative splicing and genetic variations create DC-SIGN variants found at pathogen entry sites.
Purpose of the Study:
- To investigate the expression and functional impact of DC-SIGN neck variants.
- To determine how structural differences in DC-SIGN neck regions affect multimerization and ligand binding.
- To explore the role of DC-SIGN polymorphisms in pathogen susceptibility.
Main Methods:
- Analysis of DC-SIGN expression at RNA and protein levels.
- Structural analysis of DC-SIGN multimerization.
- Characterization of naturally occurring DC-SIGN neck variants and polymorphisms.
Main Results:
- DC-SIGN neck variants are expressed on dendritic and myeloid cells.
- Multimerization depends on the lectin domain and neck region structure; glycosylation hinders oligomer formation.
- Naturally occurring variants show altered multimerization, sugar binding, and pathogen interaction capabilities.
- Allelic variants modulate DC-SIGN multimerization, impacting pathogen susceptibility.
Conclusions:
- DC-SIGN neck structure variations influence its multimerization on the cell surface.
- Polymorphisms and splicing isoforms of DC-SIGN can alter its stability and function.
- These findings provide a molecular basis for the link between DC-SIGN variations and susceptibility to HIV-1 and other infections.
Abstract:
The myeloid C-type lectin dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN, CD209) recognizes oligosaccharide ligands on clinically relevant pathogens (HIV, Mycobacterium, and Aspergillus). Alternative splicing and genomic polymorphism generate DC-SIGN mRNA variants, which have been detected at sites of pathogen entrance and transmission. We present evidence that DC-SIGN neck variants are expressed on dendritic and myeloid cells at the RNA and protein levels. Structural analysis revealed that multimerization of DC-SIGN within a cellular context depends on the lectin domain and the number and arrangement of the repeats within the neck region, whose glycosylation negatively affects oligomer formation. Naturally occurring DC-SIGN neck variants differ in multimerization competence in the cell membrane, exhibit altered sugar binding ability, and retain pathogen-interacting capacity, implying that pathogen-induced cluster formation predominates over the basal multimerization capability. Analysis of DC-SIGN neck polymorphisms indicated that the number of allelic variants is higher than previously thought and that multimerization of the prototypic molecule is modulated in the presence of allelic variants with a different neck structure. Our results demonstrate that the presence of allelic variants or a high level of expression of neck domain splicing isoforms might influence the presence and stability of DC-SIGN multimers on the cell surface, thus providing a molecular explanation for the correlation between DC-SIGN polymorphisms and altered susceptibility to HIV-1 and other pathogens.
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