Unravelling novel functions of the endosomal transporter mannose 6-phosphate/insulin-like growth factor receptor (CD222) in health and disease: An emerging regulator of the immune system

•The evolution, protein structure and genomic organization of the endosomal transporter mannose 6-phosphate/insulin-like growth factor receptor (CD222) are reviewed.•Ligands of CD222 and corresponding molecular determinants are reviewed.•Specific functions of CD222 in health and disease are reviewed.

Properly balanced cellular responses require both the mutual interactions of soluble factors with cell surface receptors and the crosstalk of intracellular molecules. In particular, immune cells exposed unceasingly to an array of positive and negative stimuli must distinguish between what has to be tolerated and attacked. Protein trafficking is one of crucial pathways involved in this labour. The approximately >270-kDa protein transporter called mannose 6- phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R, CD222) is a type I transmembrane glycoprotein present largely intracellularly in the Golgi apparatus and endosomal compartments, but also at the cell surface. It is expressed ubiquitously in a vast majority of higher eukaryotic cell types. Through binding and trafficking multiple unrelated extracellular and intracellular ligands, CD222 is involved in the regulation of a plethora of functions, and thus implicated in many physiological but also pathophysiological conditions. This review describes, first, general features of CD222, such as its evolution, genomic structure and regulation, protein structure and ligands; and second, its specific functions with a special focus on the immune system.