Aspartyl proteases target host actin nucleator complex protein to limit epithelial innate immunity

Area of Science:

• Microbiology
• Immunology
• Cell Biology

Background:

• Epithelial-immune cell interactions are vital for combating microbial infections.
• Pathogenic yeasts like Candida glabrata (Cg) can evade host defenses.
• Understanding pathogen-host signaling disruption is key to developing new therapies.

Purpose of the Study:

• To investigate how Candida glabrata Yapsins interfere with host epithelial cell signaling.
• To identify specific host targets of Cg Yapsins.
• To elucidate the mechanism by which Cg Yapsins suppress immune responses.

Main Methods:

• Investigated the interaction between Cg Yapsins and epithelial cells (ECs).
• Utilized genetic deletion mutants of Cg and host proteins (Arpc1B, p38).
• Analyzed protein degradation, signaling pathways (p38 MAPK), and cytokine secretion (IL-8).
• Assessed immune cell infiltration in a mouse infection model.

Main Results:

• Cg Yapsins degrade the epithelial cell protein Arpc1B, a subunit of the Arp2/3 complex.
• Arpc1B degradation disrupts actin assembly and reduces IL-8 secretion by ECs.
• Reduced IL-8 impairs neutrophil migration and antimicrobial activity, protecting Cg.
• Cg Yapsin-mediated Arpc1B degradation involves Arginine-142 and downregulates p38 MAPK signaling.
• Arpc1B or p38 deletion enhances Cg survival in ECs.
• In vivo studies show Cg Yapsins suppress immune cell infiltration and cytokine release in infected kidneys.

Conclusions:

• Cg Yapsins target Arpc1B to disrupt epithelial cell-neutrophil communication, promoting Cg survival.
• Arpc1B is a novel host target exploited by pathogens to suppress immune signaling.
• The findings reveal a mechanism linking Arpc1B to p38 activation and immune evasion by C. glabrata.