New Insights Relating Gasdermin B to the Onset of Childhood Asthma

Abstract

Chromosome 17q12-q21 is the most replicated genetic locus for childhood-onset asthma. Polymorphisms in this locus containing ∼10 genes interact with a variety of environmental exposures in the home and outdoors to modify asthma risk. However, the functional basis for these associations and their linkages to the environment have remained enigmatic. Within this extended region, regulation of GSDMB (gasdermin B) expression in airway epithelial cells has emerged as the primary mechanism underlying the 17q12-q21 genome-wide association study signal. Asthma-associated SNPs influence the abundance of GSDMB transcripts as well as the functional properties of GSDMB protein in airway epithelial cells. GSDMB is a member of the gasdermin family of proteins, which regulate pyroptosis and inflammatory responses to microbial infections. The aims of this review are to synthesize recent studies on the relationship of 17q12-q21 SNPs to childhood asthma and the evidence pointing to GSDMB gene expression or protein function as the underlying mechanism and to explore the potential functions of GSDMB that may influence the risk of developing asthma during childhood.

Keywords: 17q12-q21; GSDMB; asthma; gene-by-environment interaction; pyroptosis.

Figure 1.

GSDMB exon expression in lung from Genotype-Tissue Expression Analysis Release V8 (43). Full-length GSDMB transcript (top) and the alternatively spliced variant with approximate positions of rs2305480 and rs11078928 are depicted. Boxes indicate exons, and lines indicate introns. GSDMB = gasdermin B.

Figure 2.

Mechanisms of GSDMB-induced pyroptosis. In macrophages, caspase-1, 4, 5, and 11 cleave the linker domain of GSDMD and release the N terminus, which then oligomerizes to form pores in the cell membrane. This results in leakage of proinflammatory cytokines IL-1β and IL-18. The pore also allows Na⁺ efflux and K⁺ influx, leading to cell swelling and rupture. In epithelial cells, the linker domain of GSDMB is cleaved by granzyme A (from natural killer cells or cytotoxic T lymphocytes) or possibly caspase-1, leading to similar consequences. Conversely, cleavage of GSDMB by caspase-3, 4, 6, or 7 releases an incomplete N terminus fragment that cannot oligomerize to form a pore in the cell membrane. GSDMD = gasdermin D.

Figure 3.

GSDMB protein cleavage sites. Granzyme A cleaves the C-terminal domain at position 244, releasing a complete N terminus that can form a membrane pore. Caspase-1 may also cleave the linker domain to release the complete N terminus that can form the pore. In contrast, caspase-3, 6, 7, and 4 cleave GSDMB at position 91 on the N terminus, and this results in a fragment that cannot form a pore. aa = amino acids.