The exact function of human gasdermin-B (GSDMB), which regulates differentiation and growth of epithelial cells, is yet to be elucidated. In human epidermal growth factor receptor 2 (HER2)-positive breast cancer, GSDMB gene amplification and protein overexpression indicate a poor response to HER2-targeted therapy. Genome-wide association studies revealed a correlation between GSDMB SNPs and an increased susceptibility to Crohn's disease, ulcerative colitis, and asthma. The N-and C-terminal domains of all gasdermins possess lipid-binding and regulatory activities, respectively. Inflammatory caspases cleave gasdermin-D in the interdomain linker but not GSDMB. The cleaved N-terminal domain binds phosphoinositides and cardiolipin, forms membrane-disrupting pores, and executes pyroptosis. We show that both full-length GSDMB and the N-terminal domain bind to nitrocellulose membranes immobilized with phosphoinositides or sulfatide, but not with cardiolipin. In addition, the GSDMB N-terminal domain binds liposomes containing sulfatide. The crystal structure of the GSDMB C-terminal domain reveals the structural impact of the amino acids encoded by SNPs that are linked to asthma and inflammatory bowel disease (IBD). A loop that carries the polymorphism amino acids corresponding to healthy individuals (Gly299:Pro306) exhibits high conformational flexibility, whereas the loop carrying amino acids found in individuals with increased disease risk (Arg299:Ser306) exhibits a well-defined conformation and higher positive surface charge. Apoptotic executioner caspase-3, -6, and -7, but not the inflammatory caspases, cleave GSDMB at 88 DNVD 91 within the N-terminal domain. Selective sulfatide binding may indicate possible function for GSDMB in the cellular sulfatide transport.GSDMB | X-ray crystallography | disease risk polymorphism | complex trait inflammatory disease | lipid binding

Mammalian hyaluronidases hydrolyze hyaluronan, a polysaccharide of diverse physiological roles found in all tissues and body fluids. In addition to its function in normal cellular hyaluronan turnover, human hyaluronidase-1 is implicated in cancer proliferation, angiogenesis, and inflammatory diseases; its expression is up-regulated in advanced stages of bladder cancer, whereas the expression of the alternative splice-variants is down-regulated. The crystal structure reveals a molecule composed of two closely associated domains: a catalytic domain that adopts a distorted ( /R) 8 barrel resembling that of bee venom hyaluronidase, and a novel, EGF-like domain, characteristic of involvement in protein-protein interactions and regulatory processes. The structure shows that the fold of this unique EGF-like domain is intact in four alternative splice-variants, whereas the catalytic domain is likely to be unfolded. Thus, these variants may function by competing with the full-length enzyme for the putative protein partner and regulating enzymatic activity in healthy cells.Hyaluronan (HA 1 ) is a linear, unsulfated, negatively charged, glycosaminoglycan formed from ∼2000-25000 repeating disaccharide units of D-glucuronic acid (GlcUA) and N-acetyl-D-glucosamine (GlcNAc) with [GlcUA-( 1f3)-GlcNAc-( 1f4)] n linkages. HA is the major component of cartilage and serves as a joint lubricant. It controls water homeostasis in tissues and the extracellular matrix, which affects cell motility and the distribution and transport of plasma proteins. HA is also implicated in cell proliferation, differentiation, cell-cell recognition, tumor growth and invasion, angiogenesis, and inflammatory responses (1-3). The cellular role of HA and the HA-mediated signal transduction pathways depends on its size (recently reviewed by Stern et al. (4)). Large HA polymers function in organizing the extracellular matrix and serve as lubricant and shock absorber. In shock, septicemia, post surgery, blood loss, and burns, the level of circulating high molecular mass HA increases. These HA polymers are antiangiogenic, immunosuppressive, and anti-inflammatory. In contrast, HA fragments of intermediate sizes are involved in the body's alarm system. They stimulate angiogenesis and inflammatory reactions and facilitate cancer progression and invasion (4). Such HA fragments activate several cytoplasmic and extracellular signal transduction pathways associated with Raf-1 kinase, MAP kinase, and ERK. Short HA oligosaccharides are antiapoptotic and inducers of heat shock proteins. They regulate a different set of signaling molecules than the intermediate size HA including Erb2, PTEN phosphatase, and PI 3 kinase (4).Mammalian hyaluronidases are endo--N-acetyl-hexosaminidases (EC 3.2