An Intracellular Pathogen Response Pathway Promotes Proteostasis in C. elegans

Area of Science:

• Cellular Biology
• Genetics
• Molecular Biology

Background:

• Protein homeostasis (proteostasis) is vital for health; its disruption causes protein aggregate accumulation linked to aging and diseases like Alzheimer's.
• The C. elegans host response to intracellular pathogens reveals novel proteostasis mechanisms.
• Existing proteostasis pathways include heat shock and insulin signaling.

Purpose of the Study:

• To identify and characterize a novel host response pathway that enhances proteostasis capacity.
• To investigate the role of the gene pals-22 in regulating this pathway.
• To determine if this pathway is distinct from known proteostasis mechanisms.

Main Methods:

• Analysis of the transcriptional response of C. elegans to intracellular pathogen Nematocida parisii infection.
• Forward genetic screen to identify genes involved in the response.
• Characterization of pals-22 mutants, including thermotolerance assays and analysis of polyglutamine aggregates.
• Genetic analysis to determine the dependence of mutant phenotypes on cul-6.

Main Results:

• A common transcriptional response to intracellular pathogens, termed the intracellular pathogen response (IPR), was identified, including upregulation of ubiquitin ligase components like cul-6.
• The gene pals-22 was identified as a repressor of IPR gene expression.
• pals-22 mutants exhibited increased thermotolerance and reduced stress-induced polyglutamine aggregates, dependent on cul-6.
• These enhanced stress resistance phenotypes were independent of heat shock and insulin signaling pathways.

Conclusions:

• The IPR represents a novel pathway that enhances proteostasis capacity, acting parallel to well-studied pathways.
• The gene pals-22 functions as a repressor of the IPR, and its mutation confers resistance to proteotoxic stress.
• The IPR pathway, involving CUL-6 ubiquitin ligase activity, provides protection against proteotoxic stress independently of established pathways.