C-type Lectin CD209L/L-SIGN and CD209/DC-SIGN: Cell Adhesion Molecules Turned to Pathogen Recognition Receptors

Abstract

C-type lectin CD209/DC-SIGN and CD209L/L-SIGN proteins are distinct cell adhesion and pathogen recognition receptors that mediate cellular interactions and recognize a wide range of pathogens, including viruses such as SARS, SARS-CoV-2, bacteria, fungi and parasites. Pathogens exploit CD209 family proteins to promote infection and evade the immune recognition system. CD209L and CD209 are widely expressed in SARS-CoV-2 target organs and can contribute to infection and pathogenesis. CD209 family receptors are highly susceptible to alternative splicing and genomic polymorphism, which may influence virus tropism and transmission in vivo. The carbohydrate recognition domain (CRD) and the neck/repeat region represent the key features of CD209 family proteins that are also central to facilitating cellular ligand interactions and pathogen recognition. While the neck/repeat region is involved in oligomeric dimerization, the CRD recognizes the mannose-containing structures present on specific glycoproteins such as those found on the SARS-CoV-2 spike protein. Considering the role of CD209L and related proteins in diverse pathogen recognition, this review article discusses the recent advances in the cellular and biochemical characterization of CD209 and CD209L and their roles in viral uptake, which has important implications in understanding the host-pathogen interaction, the viral pathobiology and driving vaccine development of SARS-CoV-2.

Keywords: C-type lectin; C-type lectin domain family 4 member M; CD209; CD209L; CLEC4G; CLEC4M; COVID-19; DC-SIGN; L-SIGN; LSECtin; SARS-CoV-2; cell adhesion molecule.

Figure 1

CD209 family proteins. (A) Graphic presentation of CD209 family proteins and the key domain information. The schematic of domains do not directly correlate to the number of amino acids in each domain. (B) Crystal structure of a typical CRD complexed with carbohydrate and the position of the Ca²⁺ ion, which makes a tertiary complex between lectin and carbohydrate structure.

Figure 2

Amino acid sequence homology of CD209 and CD209L: (A) The schematic of CD209L is shown. (B) Alignment of the amino acids of human CD209 and CLEC4M (gene encoding for CD209L called C-type lectin domain family 4 member M, CLEC4M). The key common features of CD209L and CD209L, including potential PTMs and ion bindings are highlighted.

Figure 3

The schematics of alternatively spliced variants of CD209L and CD209. Amino acid sequences of alternatively spliced variants of CD209L (A) and CD209 (B) were aligned via Clustal Omega software program. The schematic of each alternatively variant proteins were presented.

Figure 4

Expression profile of CD209L family proteins and ACE2. (A-D) Data were extracted from the Human Expression Atlas (data was accessed in 11/03/2020) [101]. Arrowhead points to expression of individual genes in lung.

Figure 5

CD209L/L-SIGN mediates multiple cell-cell interactions between endothelial cells, DCs and T-cells. CD209L cellular ligands (ICAM2 and ICAM3) are expressed in DCs, T-cells and endothelial cells leading multiple immunoregulatory and other interactions between T-cells, DCs and endothelial cells. CD209L/ICAM2/ICAM3 interactions in endothelial cells can regulate endothelial adhesion and angiogenic properties of endothelial cells.