Extracellular proteostasis prevents aggregation during pathogenic attack.

Area of Science:

• Molecular Biology
• Cell Biology
• Immunology

Background:

• The secreted proteome is crucial for intercellular communication, innate immunity, and extracellular matrix formation in metazoans.
• Extracellular environments pose harsher conditions for proteins compared to intracellular spaces, with limited ATP availability hindering protein quality control.
• Known extracellular chaperones and proteases that prevent protein aggregation are limited.

Purpose of the Study:

• To systematically analyze the extracellular proteostasis network in Caenorhabditis elegans.
• To identify regulators of extracellular protein aggregation.
• To investigate the role of extracellular proteostasis in response to pathogens and its impact on host defense and aging.

Main Methods:

• A large-scale RNA interference screen targeting genes encoding the secreted proteome in C. elegans.
• Mimicking pathogenic attack using a pore-forming toxin to assess the response of extracellular proteostasis.
• Investigating the signaling pathways involved, specifically stress-activated MAP kinase signaling.

Main Results:

• Discovery of 57 regulators of extracellular protein aggregation, with several linked to innate immunity.
• C. elegans upregulates extracellular proteostasis components and reduces protein aggregation in response to a pore-forming toxin.
• Activation of extracellular proteostasis depends on stress-activated MAP kinase signaling.
• Overexpression of extracellular proteostasis components delays aging and confers resistance to intoxication.

Conclusions:

• Extracellular proteostasis is an active network that responds to pathogenic stimuli.
• Enhanced extracellular proteostasis contributes to systemic host defense by maintaining secreted proteome integrity and preventing proteotoxicity.
• This network plays a role in host defense, aging, and resistance to toxins.