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

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A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis Ronald A. Panganiban, PhD, Maoyun Sun, PhD, Amber Dahlin, PhD, Hae-Ryung Park, PhD, Mengyuan Kan, PhD, Blanca E. Himes, PhD, Jennifer A. Mitchel, PhD, Carlos Iribarren, MD, PhD, Eric Jorgenson, PhD, Scott H. Randell, PhD, Elliot Israel, MD, Kelan Tantisira, MD, Stephanie Shore, PhD, Jin-Ah Park, PhD, Scott T. Weiss, MD, Ann Chen Wu, MD, Quan Lu, PhD Journal of Allergy and Clinical Immunology Volume 142, Issue 5, Pages 1469-1478.e2 (November 2018) DOI: 10.1016/j.jaci.2017.11.040 Copyright © 2018 The Authors Terms and Conditions

Journal of Allergy and Clinical Immunology 2018 142, 1469-1478 Journal of Allergy and Clinical Immunology 2018 142, 1469-1478.e2DOI: (10.1016/j.jaci.2017.11.040) Copyright © 2018 The Authors Terms and Conditions

Fig 1 GSDMB expression in airway epithelium. A, Relative GSDMB mRNA expression in human primary airway smooth muscle (ASM), lung fibroblasts (FIB), and NHBE cells over the course of ALI culture. ACTB (β-actin) was used as an internal control. B, Relative GSDMB mRNA expression in sorted β-tubulin IV-positive ciliated NHBE and MUC5AC-postive goblet NHBE cells. Graphs show mean of fold-change from 3 different donors (n = 3) ± SEM. C and D, Immunostaining of GSDMB protein in NHBE cells at day 21 of ALI culture (Fig 1, C) and lung tissue (Fig 1, D) shows GSDMB expression in ciliated cells. Ciliated cells were stained for β-tubulin IV and nuclei were visualized by DAPI staining. DAPI, 4′-6-Diamidino-2-phenylindole, dihydrochloride; n.s., nonsignificant. Journal of Allergy and Clinical Immunology 2018 142, 1469-1478.e2DOI: (10.1016/j.jaci.2017.11.040) Copyright © 2018 The Authors Terms and Conditions

Fig 2 GSDMB is cleaved by caspase 1 to induce pyroptosis. A, Western blot showing GSDMB cleavage by caspase-1. WT or mutant forms (D236A and D250A) were cotransfected with either caspase-1 or vector plasmid. Twenty-four hour posttransfection, protein lysates were prepared for Western blotting. B and C, The N-terminal fragment of GSDMB induces cell death. HEK293T cells were transfected with EGFP, full-length GSDMB, N-terminal, or C-terminal fragment of GSDMB protein. Twenty-four hours after transfection, cytotoxicity was assessed using the LDH assay (Fig 2, B) and changes in cell morphology were captured by light microscopy (Fig 2, C). D, LDH assay showing GSDMB-induced pyroptosis in the presence of caspase-1. HEK293T cells were transfected with WT, D236A or D250A GSDMB (all full length) in the presence or absence of caspase-1. Twenty-four hours after transfection, cytotoxicity was assessed using the LDH assay. EGFP, Enhanced green fluorescent protein; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HEK293T, human embryonic kidney 293T; MW, molecular weight; NS, nonsignificant; WT, wild-type. Graph shows mean of n = 3 ± SEM from a representative experiment. *P < .05. Journal of Allergy and Clinical Immunology 2018 142, 1469-1478.e2DOI: (10.1016/j.jaci.2017.11.040) Copyright © 2018 The Authors Terms and Conditions

Fig 3 Splice variant rs11078928 abolishes pyroptosis activity of GSDMB. A, Schematic representation of the GSDMB gene showing the exons and the 2 translational products. Boxes: exons; *rs11078928. (B) RT-PCR and (C) Western blot showing the effect of rs11078928 on GSDMB splicing and expression in NHBE cells harboring the TT or CC allele and cultured in ALI. D, The 403 variant does not induce caspase-1–mediated pyroptosis in HEK293T cells. LDH assay was performed 24 hours posttransfection with the indicated constructs. E, Cytotoxic effects of N-terminal fragments (N232: residues 1-232; N220: residues 1-220) transfected in HEK293T cells. LDH assay was performed 24 hours posttransfection. F, Effect of the expected product of rs11078928 on inflammasome-induced pyroptosis. BEAS2B or 16HBE cells transfected with EGFP, 416, or 403 and caspase-1 were treated with 10 μM nigericin. EGFP, Enhanced green fluorescent protein; HEK293T, human embryonic kidney 293T; NS, nonsignificant. Graph shows mean of n = 3 ± SEM from a representative experiment. *P < .05. Journal of Allergy and Clinical Immunology 2018 142, 1469-1478.e2DOI: (10.1016/j.jaci.2017.11.040) Copyright © 2018 The Authors Terms and Conditions

Fig E1 LD map of coding GSDMB SNPs and other coding SNPs in the 17q21 region. Genotype data used to evaluate LD are from CEU 1000 Genomes. Numbers represent r2 of 2 SNPs. Journal of Allergy and Clinical Immunology 2018 142, 1469-1478.e2DOI: (10.1016/j.jaci.2017.11.040) Copyright © 2018 The Authors Terms and Conditions