Human GBP1 is a microbe-specific gatekeeper of macrophage apoptosis and pyroptosis

Area of Science:

• Immunology
• Cell Biology
• Microbiology

Background:

• Guanylate binding proteins (GBPs) are interferon-inducible GTPases crucial for antimicrobial immunity.
• Human GBP2 and GBP5 activate inflammasomes and caspase-4, leading to pyroptosis during bacterial infections.
• The mechanisms of macrophage death induced by the parasite Toxoplasma gondii remain largely unknown.

Purpose of the Study:

• To investigate the role of GBPs, specifically GBP1, in regulating cell death pathways induced by microbial pathogens.
• To elucidate the molecular mechanisms by which GBP1 controls Toxoplasma gondii- and Salmonella-induced cell death in human macrophages.

Main Methods:

• Utilized human macrophage cell lines and infection models with Toxoplasma gondii and Salmonella.
• Employed genetic manipulation (e.g., gene silencing) to assess the requirement of GBP1 in cell death.
• Investigated the subcellular localization of GBP1 and its interaction with pathogen-containing vacuoles.
• Analyzed the involvement of inflammasome components (AIM2, ASC, caspase-8, caspase-4) and cell death executioners (GSDMD).

Main Results:

• Toxoplasma gondii-induced macrophage death necessitates GBP1, which targets the parasitophorous vacuole via GTPase activity and prenylation.
• GBP1 facilitates AIM2 inflammasome activation, leading to GSDMD-independent, ASC- and caspase-8-dependent apoptosis.
• GBP1 also targets Salmonella-containing vacuoles, enhancing caspase-4 activation and pyroptosis.
• GBP1's role in pathogen detection is linked to its ability to liberate microbial molecules, as bypassing this function prevents GBP1-mediated cell death induction.

Conclusions:

• GBP1 functions as a critical gatekeeper, directing specific cell death responses (apoptosis or pyroptosis) based on the infecting microbe.
• This study expands the known immune functions of human GBPs beyond pyroptosis to include the regulation of apoptosis.
• GBP1's mechanisms of action highlight its importance in innate immunity against diverse microbial pathogens.