Structural basis for GSDMB pore formation and its targeting by IpaH7.8.

Area of Science:

• Molecular biology
• Immunology
• Structural biology

Background:

• Gasdermins (GSDMs) are pore-forming proteins crucial for pyroptosis, a host defense mechanism.
• GSDMB's unique properties and pyroptotic potential are debated, though it exhibits direct bactericidal activity.
• Shigella evades GSDMB-mediated defense via the effector IpaH7.8, which targets GSDMB for degradation.

Purpose of the Study:

• To elucidate the structural basis of Shigella IpaH7.8 recognition and targeting of GSDMB.
• To investigate the structural regulation of GSDMB pore formation and pyroptotic activity.

Main Methods:

• Cryogenic electron microscopy (cryo-EM) was used to determine the structures of GSDMB-IpaH7.8 complex and the GSDMB pore.
• Structural analysis identified key residues and motifs involved in protein-protein interactions and regulation.

Main Results:

• The cryo-EM structure revealed a motif of three negatively charged residues in GSDMB recognized by Shigella IpaH7.8, explaining species specificity.
• The GSDMB pore structure highlighted the role of the alternative splicing-regulated interdomain linker in modulating pyroptotic activity.
• GSDMB isoforms with canonical linkers showed normal pyroptosis, while others had attenuated or no activity.

Conclusions:

• This study reveals the molecular mechanisms by which Shigella IpaH7.8 targets GSDMB.
• A specific structural motif in GSDMB is critical for IpaH7.8 recognition and dictates species specificity.
• Alternative splicing of the GSDMB interdomain linker significantly impacts its pyroptotic function.