Inefficient SRP Interaction with a Nascent Chain Triggers a mRNA Quality Control Pathway

Misfolded proteins are often cytotoxic, unless cellular systems prevent their accumulation. Data presented here uncover a mechanism by which defects in secretory proteins lead to a dramatic reduction in their mRNAs and protein expression. When mutant signal sequences fail to bind to the signal recognition particle (SRP) at the ribosome exit site, the nascent chain instead contacts Argonaute2 (Ago2), and the mutant mRNAs are specifically degraded. Severity of signal sequence mutations correlated with increased proximity of Ago2 to nascent chain and mRNA degradation. Ago2 knockdown inhibited degradation of the mutant mRNA, while overexpression of Ago2 or knockdown of SRP54 promoted degradation of secretory protein mRNA. The results reveal a previously unappreciated general mechanism of translational quality control, in which specific mRNA degradation preemptively regulates aberrant protein production (RAPP). [Display omitted] •Mechanism for regulation of aberrant protein production (RAPP) is described•Mutations in the signal sequence shift proximity from SRP to Ago2•Defective SRP-nascent chain interactions trigger degradation of the encoding mRNA•Ago2 is required for the specific degradation of the mutant mRNA An Ago2-dependent translational quality control pathway degrades mRNAs of secretory proteins that fail to bind the signal recognition particle at the ribosome exit site.