Regulating GSDMB pore formation: to ignite or inhibit?

Abstract

In the recent Nature, Wang et al. and Zhong et al. present the cryo-EM structures of Gasdermin B (GSDMB) pore and strucures of GSDMB in complex with a Shigella effector, IpaH7.8. The structures shed light on the structural mechanisms that govern GSDMB-mediated pyroptosis, a process that is regulated by pathogenic bacteria and alternative splicing.

Fig. 1. GSDMB pore formation is regulated by alternative splicing and bacterial effector IpaH7.8.

In humans, there exist six splicing transcripts for GSDMB, with isoforms 1–4 and 6 containing conserved N- and C-terminal domains that differ in their interdomain linker. Isoform 5, on the other hand, only contains the C-terminal domain. GSDMB isoforms 4 and 6, which possess the canonical interdomain linker, are capable of inducing pyroptotic cell death and killing intracellular bacteria. Meanwhile, GSDMB isoform 1 has an alternative interdomain linker with a four-amino-acid insertion and displays reduced pore-forming activity that is insufficient to induce pyroptosis but is enough to kill bacteria. GSDMB isoforms 2 and 3 lack the entire canonical sequence in the interdomain linker and exhibit no pore-forming activity. Additionally, the Shigella effector IpaH7.8 efficiently inhibits the pore-forming activity of GSDMB by binding to GSDMB-N and through the ubiquitination of GSDMB transmembrane region. (The figure was created in Biorender.).