Sialic Acids in Membrane Organization and Receptor Function: Integrins and CD22

The plasma membrane contains a wide array of glycans and glycolipids, many of which are capped by sialic acids (also called neuraminic acid). As a result, sialic acids are front-line mediators of interactions between the extracellular surface and the external environment. Examples include host-pathogen interactions (e.g. influenza) and the recognition of host cells by leukocytes (white blood cells). Thus, the composition of sialosides in the membrane can influence receptor-receptor interactions critical to immunity and cellular function. Our group is investigating the influence of sialic acid on the function of adhesion and immune receptors through the development of tools that alter catabolism of membrane sialosides. The human neuraminidases (NEU) are a family of four isoenzymes (NEU1, NEU2, NEU3, and NEU4) which have a range of substrate preferences as well as cellular and tissue localization. Our group has developed a panel of selective inhibitors, many with nanomolar potency, are being used to investigate how degradation of sialosides influences the function of cellular receptors. We use fluorescence microscopy to measure the size of receptor clusters and lateral mobility of receptors. These biophysical methods provide critical insight into the influence of NEU activity on membrane receptor organization. We have examined the role of NEU enzymes on the function and organization of leukocyte adhesion receptors. We find that specific NEU enzymes can modulate integrin adhesion and affect leukocyte transmigration. In related work, we have examined the influence of synthetic glycoconjugates and inhibitors of NEU on the organization of the CD22 receptor of B cells. We propose that understanding the specific roles of NEU isoenzymes will identify new therapeutic strategies for autoimmunity, inflammation, and cancer.