ZAP is critical for mRNA quality control through the regulation of aberrant protein pathway

The endoplasmic reticulum (ER) is a critical site for accurate folding and processing of secretory and membrane proteins. Signal peptides within such proteins are recognized by the signal recognition particle (SRP) which guides them to the ER. When this process is impaired, cells rely on quality control mechanisms to prevent the accumulation of misfolded or mislocalized proteins. A critical mechanism, known as regulation of aberrant protein production (RAPP), targets mRNAs encoding mutated signal peptides and their corresponding aberrant proteins. Using a functional genetic screen, we identify the zinc finger antiviral protein (ZAP) as a key component of the RAPP pathway. Proteomics and enhanced UV crosslinking and immunoprecipitation (eCLIP) experiments reveal that the ZAP-S isoform associates with SRP components and facilitates degradation of aberrant mRNAs and proteins. ZAP-S recognizes faulty proteins early in their biogenesis and targets the mRNAs encoding them for degradation. Loss of ZAP-S activates the unfolded protein response and the downstream integrated stress response, highlighting its central role in safeguarding protein targeting and maintaining cellular homeostasis.