title: d-Ribose glycates β(2)-microglobulin to form aggregates with high cytotoxicity through a ROS-mediated pathway.
abstract: β(2)-Microglobulin (β(2)M) modified with advanced glycation end products (AGEs) is a major component of the amyloid deposits in hemodialysis-associated amyloidosis (HAA). However, the effect of glycation on the misfolding and aggregation of β(2)M has not been studied so far. Here we examine the molecular mechanism of aggregate formation of HAA-related ribosylated β(2)M in vitro. We find that the glycating agent d-ribose interacts with human β(2)M to generate AGEs that form aggregates in a time-dependent manner. Ribosylated β(2)M molecules are highly oligomerized compared with unglycated β(2)M, and have granular morphology. Furthermore, such ribosylated β(2)M aggregates show significant cytotoxicity to both human SH-SY5Y neuroblastoma and human foreskin fibroblast FS2 cells and induce intracellular reactive oxygen species (ROS). Presence of the antioxidant N-acetylcysteine (1.0mM) attenuated intracellular ROS and prevented cell death induction in both SH-SY5Y and FS2 cells, indicating that the cytotoxicity of ribosylated β(2)M aggregates depends on a ROS-mediated pathway in both cell lines. In other words, d-ribose reacts with β(2)M and induces the ribosylated protein to form granular aggregates with high cytotoxicity through a ROS-mediated pathway. These findings suggest that ribosylated β(2)M aggregates could contribute to the dysfunction and death of cells and could play an important role in the pathogenesis of β(2)M-associated diseases such as HAA.
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, China.
authors.forename: Fan-Lou
authors.initials: FL
authors.lastname: Kong
authors.forename: Wei
authors.initials: W
authors.lastname: Cheng
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Liang
mesh_terms: D000686:Amyloidosis / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D018625:Microscopy, Atomic Force; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012266:Ribose / Q000737:chemistry / Q000378:metabolism*; D013997:Time Factors; D001613:beta 2-Microglobulin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D017127:Glycation End Products, Advanced; D017382:Reactive Oxygen Species; D001613:beta 2-Microglobulin; D012266:Ribose