FIG 8.

Summary of proposed 7,9-O- and 9-O-acetyl sialic acid production and trafficking in cells. (Step 1) Sia (purple diamond) is added to the growing glycan chain in the Golgi by sialyltransferases using CMP-Neu5Ac or CMP-Neu5Gc substrates, which are synthesized in the nucleus by the addition of cytodine monophosphate (CMP) to Neu5Ac or Neu5Gc and are specifically imported into the Golgi. (Step 2) CMP-Neu5Ac or CMP-Neu5Gc Sia are modified by CasD1, adding one or two acetyl groups to form 9-O-Ac or 7,9-O-Ac, respectively (red circles), before being added to glycan chains. The majority of glycoproteins with these modifications are retained in the Golgi compartment (large arrow) of many cells, including the HEK-293 and A549 cells examined here, whereas only some (mostly 9-O-Ac) are transported to the cell surface (small arrow). (Step 3) Surface-displayed O-acetyl Sia can interact with pathogens, cell receptors, or lectins. For example, ICV uses 9-O-Ac as its receptor. Secreted forms of SIAE may also remove the O-acetyl modifications, altering these lectin-ligand interactions. (Step 4) When glycoproteins are recycled from the cell surface, the lysosomal form of SIAE (LSE) can remove O-acetyl modifications from Sia. Free Sia are exported to the cytosol, where the cytosolic form of SIAE (CSE) can also remove any remaining O-acetyl modifications. Unmodified Sia can then be “activated” in the nucleus by the addition of CMP and transported to the Golgi compartment for addition to new glycan chains.