Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein

Abstract

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

A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis

“…3D). GSDMB-416 P311S (proline to serine change at residue 311), which was suggested to affect GSDMB protein conformation 44 , induced similar cytotoxicity as the wild type protein (Fig. 3D), indicating that rs2305480 has little effect on the pyroptotic activity of GSDMB.…”

“…Another study showed that the asthma risk allele (T) of rs11078928 was associated with increased expression of GSDMB transcripts 43 . More recently, Chao et al reported that several apoptotic executioner caspases can cleave the GSDMB protein 44 . In addition, Das et al showed that GSDMB is expressed in human airway epithelial cells and that GSDMB expression increases with severity of asthma 33 .…”

Gasdermins: Effectors of Pyroptosis

“…While one group did not observe significant expression of gasdermin B in the lung[49], another group did observe gasdermin B in the lung and implicated it in influencing expression of genes related to airway remodeling and hyper-responsiveness[53]. Furthermore, one disease-associated SNP causes an alteration in the conformational flexibility and surface charge of a region in the RD[54]. The GSDMB SNPs and the GSDMB region of chromosome 17q21 have been associated with several other immune diseases as well[55–62].…”

“…A recent report shows that gasdermin B can be cleaved by caspase-3, -6, and -7 within the PFD[54], similar to PFD cleavage of gasdermin D[12]. Thus, both gasdermin B and gasdermin D may be inactivated during apoptosis to prevent pyroptosis after caspase-3 activates (although this idea is must be reconciled with caspase-3 activating gasdermin E, see below).…”

Target highlights from the first post‐PSI CASP experiment (CASP12, May–August 2016)

“…However, because of linkage disequilibrium within the genome SNPs the challenge for the large‐scale genome sequencing is to reveal the disease causative SNPs. The structural studies of GSDMB_C were undertaken to provide insights into possible mechanisms that the SNPs may contribute to disease risk …”