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Background
Glycosphingolipids are amphipathic lipids whose parent compound is ceramide, a sphingosine and a fatty acid bonded by an amide bond. Ceramides are the hydrophobic "tail" that's inside the membrane lipid bilayer as membrane building blocks. Hydrophilic oligosaccharide chains are bound to the serine in the ceramide and together with the serine they compose the polar "head" projecting out on the cell surface into the external environment. Apart from their structure as cell membranes, glycosphingolipids are also involved in cell proliferation, differentiation, movement, morphogenesis, transport between and among cells and matrix molecules, and even the formation and functioning of the nervous system.
Globotriaosylceramide (Gb3) is a neutral glycosphingolipid found in mammalian cell membranes, it's widely distributed in central nervous cells, kidney endothelial cells, intestinal epithelial cells, some tumour cells. It is very much involved in the growth, differentiation, identification and signalling of cells. Gb3 has been renamed according to the cell that it first appeared in; for erythrocytes, it's called the Pk blood group antigen, for lymphocytes the CD77 differentiation antigen, and for endothelial cells the Shiga toxin (STx) receptor. In Golgi, lactose ceramide α1→4 galactosyltransferase (i.e., Gb3 synthase) catalyzes the formation of Gb3 from uracil diphosphate galactose and LacCer. Gb3 reaches the surface of the plasma membrane mainly through vesicular transport. Gb3 on the cell membrane surface is in dynamic equilibrium, with newly synthesized Gb3 being translocated along the efflux pathway to the cell membrane, while membrane Gb3 is translocated along the endocytosis pathway via the endosomes to the lysosome or Golgi apparatus and the endoplasmic reticulum.
Gb3 is the predominant known receptor for STx on the cell membrane and, by binding to STxB, assists in the internalization of the toxin thereby exerting its toxic effects and causing a range of intestinal disorders. After binding to Gb3, STx is mainly cytosolized in a clathrin-dependent form, traveling from the surface of the plasma membrane to the Golgi apparatus via the endosomes. Then STx is released backward to the endoplasmic reticulum. After STx reaches the endoplasmic reticulum, chaperone molecules and proteases in the endoplasmic reticulum reduce the disulfide bond between A and B to unbind the A and B subunits. The STxA subunit goes into the cytoplasm to work its magic.
Figure 1. Overview of the intracellular trafficking of Stxs (Source: Robert A, et al. 2021)
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References
A single point mutation in the gene encoding Gb3/CD77 synthase causes a rare inherited polyagglutination syndrome (vol 287, pg 38220, 2012)
Ligation of centrocyte/centroblast marker 1 on Epstein-Barr virus-transformed B lymphocytes induces cell death in a reactive oxygen species-dependent manner
HUMAN IMMUNOLOGY
Authors: Kim, Yeong Seok; Park, Ga Bin; Choi, Young Mi; Kwon, Oh Suk; Song, Hyun Keun; Kang, Jae Seung; Kim, Young In; Lee, Wang Jae; Hur, Dae Young
After primary infection of B cells with Epstein-Barr virus (EBV), infected B cells express several viral homologs of human genes that promote activation (LMP1 and CD40) or survival (BHRF and BCL2). EBV-infected B cells also express germinal center phenotype markers, such as CD77, PNA, CD95, and CD38. This transformation of B cells by EBV infection resembles normal B-cell activation and differentiation arising in the germinal center. In the present study, we found that EBV-transformed B cells expressed centrocyte/centroblast marker 1 (CM1), a possible marker of GC B cells and an inducer of their apoptosis. Moreover, ligation of CM1 on EBV-transformed B cells by immobilized anti-CM1 monoclonal antibody induced cell death. The ligation of CM1 immediately increased the generation of intracellular reactive oxygen species (ROS) and disrupted the mitochondrial membrane potential. Pretreatment with N-acetyl cystein (an ROS inhibitor) almost completely blocked this cell death, but Z-VAD-fmk (a caspase inhibitor) did not, We further investigated whether apoptosis-inducing factor (AIF) and endonuclease G (EndoG), which are both related to caspase-independent cell death, would be translocated to the nucleus during the ligation of CM1. We found that AIF and EndoG were released to the cytosplam but not translocated to the nucleus. Moreover, cytochalasin D, a cytoskeleton disruptor, rescued the cells from CM1-mediated cell death and blocked ROS generation. Therefore, it is conceivable that CM1 signaling might provoke cytoskeleton polymerization and trigger ROS generation. Taking these observations together, we conclude that the ligation of CM1 on EBV-transformed B cells can cause cell death via the ROS produced by F-actin polymerization in a caspase-independent manner, although this cell death might be unrelated to AIF and EndoG release from the mitochondria.
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Figure 1. Overview of the intracellular trafficking of Stxs
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