Inefficient SRP interaction with a nascent chain triggers a mRNA quality control pathway

Area of Science:

• Molecular Biology
• Cellular Biology
• Protein Homeostasis

Background:

• Misfolded proteins can be cytotoxic if cellular systems fail to prevent their accumulation.
• Secretory proteins require specific pathways for proper folding and translocation.
• Existing quality control mechanisms primarily focus on protein folding and degradation.

Purpose of the Study:

• To uncover a novel mechanism by which defects in secretory proteins reduce mRNA and protein expression.
• To elucidate the role of Argonaute2 (Ago2) in response to aberrant secretory protein synthesis.
• To characterize a new translational quality control pathway that preemptively regulates aberrant protein production (RAPP).

Main Methods:

• Investigated the interaction between nascent secretory protein chains, signal recognition particle (SRP), and Argonaute2 (Ago2) at the ribosome exit site.
• Utilized Argonaute2 (Ago2) knockdown and overexpression experiments to assess its role in mRNA degradation.
• Performed SRP54 knockdown to evaluate its influence on secretory protein mRNA stability.

Main Results:

• Mutant signal sequences that fail to bind SRP lead to nascent chain contact with Ago2.
• This interaction specifically triggers the degradation of mutant secretory protein mRNAs.
• The severity of signal sequence mutations correlates with Ago2 proximity and mRNA degradation; Ago2 knockdown inhibits degradation, while Ago2 overexpression or SRP54 knockdown promotes it.

Conclusions:

• A novel translational quality control mechanism, termed preemptively regulates aberrant protein production (RAPP), has been identified.
• Ago2 plays a critical role in recognizing and degrading mRNAs encoding aberrant secretory proteins.
• This pathway represents a previously unappreciated general mechanism for controlling protein production at the mRNA level.