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.).