DC-SIGN and L-SIGN: the SIGNs for infection
Ui-Soon Khoo1, Kelvin Y K Chan, Vera S F Chan
1Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, University Pathology Building, Hong Kong, SAR, China. uskhoo@pathology.hku.hk
Insights
Dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) and liver/lymph node-specific ICAM-3 grabbing non-integrin (L-SIGN) receptors have distinct ligand-binding properties due to variations in their neck regions, influencing pathogen recognition.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) and liver/lymph node-specific ICAM-3 grabbing non-integrin (L-SIGN) are C-type lectins involved in pathogen recognition.
- These receptors were previously thought to have similar structures and ligand-binding characteristics.
Purpose of the Study:
- To review recent biochemical and structural studies on DC-SIGN and L-SIGN.
- To highlight the distinct ligand-binding properties and physiological functions of these receptors.
- To investigate the role of the extracellular neck region in pathogen binding and evolutionary selection.
Main Methods:
- Biochemical and structural studies of DC-SIGN and L-SIGN.
- Analysis of the extracellular neck region, including tandem repeats and polymorphisms.
- Functional studies on pathogen binding.
- Genetic association studies and demographic analysis of neck region variants.
Main Results:
- DC-SIGN and L-SIGN exhibit distinct ligand-binding properties and physiological functions.
- The extracellular neck region, encoded by tandem repeats, significantly influences pathogen-binding.
- L-SIGN displays considerable polymorphism in its neck region, affecting ligand-binding affinity.
- Distinct neck-region allele and genotype distributions are observed among different ethnic groups.
Conclusions:
- The neck region of DC-SIGN and L-SIGN is a key determinant of their distinct ligand-binding specificities.
- Polymorphism in the L-SIGN neck region impacts ligand-binding affinity and may contribute to differential susceptibility to infections.
- The neck region is a potential target for pathogen-driven selective pressures, as evidenced by demographic data.
Abstract:
Two closely related trans-membrane C-type lectins dendritic cell-specific intracellular adhesion molecules (ICAM)-3 grabbing non-integrin (DC-SIGN or CD209) and liver/lymph node-specific ICAM-3 grabbing non-integrin (L-SIGN also known as DC-SIGNR, CD209L or CLEC4M) directly recognize a wide range of micro-organisms of major impact on public health. Both genes have long been considered to share similar overall structure and ligand-binding characteristics. This review presents more recent biochemical and structural studies, which show that they have distinct ligand-binding properties and different physiological functions. Of importance in both these genes is the presence of an extra-cellular domain consisting of an extended neck region encoded by tandem repeats that support the carbohydrate-recognition domain, which plays a crucial role in influencing the pathogen-binding properties of these receptors. The notable difference between these two genes is in this extra-cellular domain. Whilst the tandem-neck-repeat region remains relatively constant size for DC-SIGN, there is considerable polymorphism for L-SIGN. Homo-oligomerization of the neck region of L-SIGN has been shown to be important for high-affinity ligand binding, and heterozygous expression of the polymorphic variants of L-SIGN in which neck lengths differ could thus affect ligand-binding affinity. Functional studies on the effect of this tandem-neck-repeat region on pathogen-binding, as well as genetic association studies for various infectious diseases and among different populations, are discussed. Worldwide demographic data of the tandem-neck-repeat region showing distinct differences in the neck-region allele and genotype distribution among different ethnic groups are presented. These findings support the neck region as an excellent candidate acting as a functional target for selective pressures exerted by pathogens.
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