Mouse LSECtin as a model for a human Ebola virus receptor

Pipirou, Zoi; Powlesland, Alex S; Steffen, Imke; Pöhlmann, Stefan; Taylor, Maureen E; Drickamer, Kurt

The close similarity in the biochemical properties of human and mouse LSECtin is in stark contrast to the widely divergent properties of the mouse orthologs of DC-SIGN. The difference in the evolutionary history of these two protein families, in spite of their proximity in mammalian genomes, indicates that these proteins are subject to different Mouse LSECtin evolutionary pressures. One interpretation of the conserved binding properties of LSECtin is that this receptor may bind a conserved endogenous glycan ligand, whereas DC-SIGN is evolving to interact with different pathogen glycans. This interpretation is consistent with the fact that DC-SIGN functions as an endocytic receptor able to a direct pathogen uptake and presentation to the immune system (Engering et al. 2002; Guo et al. 2004) , whereas LSECtin does not have constitutive endocytic activity (Gramberg et al. 2008; Powlesland et al. 2008) . In this scenario, the binding of endogenous ligands, such as CD44 on T cells, would be the primary function of LSECtin, which has been hijacked by certain pathogens such as Ebola virus. Few other glycan-binding receptors show such conserved properties between species as is documented here for LSECtin. DC-SIGN is one of many receptors that show extreme divergence between human and mouse (Powlesland et al. 2006) . The CD33 family of siglecs represent another example of independent radiation of a group of glycanbinding receptors (Crocker et al. 2007) , and some receptors, such as the Kupffer cell receptor and prolectin, are present in rodents but not humans or vice versa (Fadden et al. 2003; Graham et al. 2009 ). Aside from the evolutionary and functional implications of the conservation of LSECtin function, the close similarities in their ligand-binding properties, as well as the similar restricted distribution of tissues in which they are expressed, provide a firm foundation for use of mouse LSECtin as a model for the human receptor, which is not always possible in the case of more divergent receptors. The development of low-molecular-weight inhibitors that work equally well on the human and mouse proteins, as well as the description of mice in which LSECtin has been knocked out (Tang et al. 2009 ), thus provide opportunities for exploring the physiological functions of the human receptor using mouse models.