A critical feature of Alzheimer's disease (AD) is the deposition of Amyloid plaque, high levels of amyloid beta-peptide, Aβ. BACE 1 protease initiates the formation of Aβ from β-Amyloid precursor protein (APP). We recently showed that BALE 1 is also involved in the cleavage and secretion of ST6Gal I, sialyltransferase that modifies N-linked oligosaccharide. In this review, first of all, I describe how we previously found that BACE1 is involved in the cleavage and secretion of ST6Gal I. Next, I report our recent data showing that cleaved ST6Gal I by BALE1 is not simply secreted out of the cell, but the enzyme receives a subsequent processing event before its secretion.
Lipid rafts are cholesterol and glycosphingolipid-rich subdomains of the plasma membrane. Various molecules including those involved in signal transduction and pathology localize into the microdomain. Dynamic assemblies of lipid rafts with these molecules by intracellular or extracellular events conduct signaling and sequentially regulate certain physical responses. Furthermore, several microorganisms have been found to handle lipid rafts for their infections. This review provides several examples of dynamic raft functions in signaling regulation and in the molecular mechanisms in diseases such as Alzheimer's disease and viral infections.
Protein-carbohydrate interactions serve a variety of functions in the immune system. A number of lectins mediate both pathogen recognition and cell-to-cell interactions using structurally related carbohydrate recognition domains (CRDs). Macrophage galactose-type C-type lectin (MGL) was previously believed to be derived from a single gene. However, we describe the properties of another novel MΦ galactose-type C-type lectin, mMGL2. As an obvious consequence, the previous mMGL must now be called mMGL1. These lectins are highly homologous to each other except in their cytoplasmic domains and CRDs. The mMGL2 mRNA was also detected in mMGL1-positive cells. We found that mMGL2 has distinct carbohydrate specificity from mMGL1. These two lectins may function cooperatively as recognition and endocytic molecules on macrophages and bone marrow-derived immature dendritic cells.
The sulfation state of glucosamine residues within heparan sulfate proteoglycans (HSPGs) is known to be critical for the binding of many growth and differentiation factors and for signaling by some factors. Recently, we cloned two novel extracellular sulfatases (Sulf 1 and Sulf 2) in human and mouse (1) following the identification of orthologues of one of them in quail and rat. These sulfatases are distinct from classical intracellular sulfatases, which are mainly located in lysosomes and function in the breakdown of sulfated macromolecules. The novel sulfatases possess two regions of high homology to the human glucosamine-6-sulfatase. The Sulfs can function as endosulfatases against heparin. An interesting possibility is that the extracellular sulfatases have analogous functions during development and during tumor formation, i.e. regulating the bioavailability of heparin-binding growth/differentiation factors. Consistent with a role for the Sulfs in tumor formation, we have detected increased levels of Sulf mRNAs in several tumors compared to normal tissues.