Fungal Als proteins hijack host death effector domains to promote inflammasome signaling

Area of Science:

• Microbiology
• Immunology
• Cell Biology

Background:

• High-damaging Candida albicans strains form hyphae, exacerbating intestinal inflammation in ulcerative colitis via IL-1β-dependent pathways.
• Fungal agglutinin-like sequence (Als) proteins are implicated in worsening colitis models, and FADD and caspase-8 are key regulators of gut homeostasis.

Purpose of the Study:

• To investigate the direct link between fungal Als proteins and the host immune response, specifically focusing on IL-1β release and cell death pathways.
• To elucidate the mechanism by which Als proteins interact with caspase-8, FADD, and the inflammasome components.

Main Methods:

• Investigated Als protein interaction with caspase-8, ASC, and FADD in immune and non-immune cells.
• Utilized mouse models of DSS-induced colitis and human cell lines (macrophages, Jurkat cells).
• Assessed IL-1β release, ASC oligomerization, and apoptosis induction/inhibition.

Main Results:

• Als proteins, particularly hyphal Als3, induce IL-1β release from immune cells.
• Als3 interacts with caspase-8 and ASC in macrophages, with caspase-8 being crucial for IL-1β processing.
• In non-immune cells, Als3 associates with FADD and caspase-8, and N-terminal Als3 inhibits apoptosis by promoting FADD/caspase-8 oligomerization via death effector domains (DEDs).

Conclusions:

• Als proteins act as intracellular sensors through their DED-binding interactions, modulating host inflammatory and apoptotic pathways.
• This study identifies Als3-FADD/caspase-8 interactions as a critical mechanism in fungal-mediated gut inflammation.
• Targeting these fungal protein-host interactions offers potential therapeutic strategies for ulcerative colitis and other inflammatory conditions.