Proteostasis is differentially modulated by inhibition of translation initiation or elongation

Area of Science:

• Cellular Biology
• Molecular Biology
• Genetics

Background:

• mRNA translation plays a crucial role in maintaining proteostasis.
• Understanding how specific translation steps impact proteostasis is key to developing therapeutic strategies.

Purpose of the Study:

• To compare the distinct protective profiles of inhibiting translation initiation versus elongation in Caenorhabditis elegans under proteotoxic stress.
• To investigate the role of HSF-1 in the interplay between translation and proteostasis.

Main Methods:

• Utilizing chemical inhibitors targeting discrete steps of mRNA translation (initiation and elongation).
• Challenging proteostasis in C. elegans using various stress conditions (heat, proteasome dysfunction, age-associated protein aggregation).
• Assessing lifespan and protein aggregation phenotypes in wild-type and hsf-1 mutant C. elegans.

Main Results:

• Inhibiting elongation protected against heat and proteasome dysfunction independently of HSF-1 but not age-associated aggregation.
• Inhibiting initiation protected against heat and age-associated aggregation, increasing lifespan, in an HSF-1-dependent manner.
• HSF-1 is required for translation initiation inhibition to reduce newly synthesized protein levels, suggesting a cooperative role.

Conclusions:

• Distinct translation steps confer differential proteostasis benefits.
• The HSF-1 pathway cooperates with translation initiation machinery to regulate protein synthesis and restore proteostasis.
• Targeting translation initiation offers a promising avenue for interventions against age-related proteotoxicity.