ZAP targets aberrant mRNA transcripts encoding proteins with defective signal peptides for degradation.

The endoplasmic reticulum (ER) is an important 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. One of these mechanisms, known as regulation of aberrant protein production (RAPP), detects nascent proteins with aberrant signal peptides and degrades their mRNA templates. Using functional genetic screens, 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 short isoform ZAP-S associates with SRP components and facilitates degradation of aberrant mRNAs. ZAP-S recognizes faulty proteins early in their biogenesis and targets their corresponding mRNAs for degradation. Loss of ZAP activates the unfolded protein response and the downstream integrated stress response, highlighting its central role in safeguarding protein targeting and maintaining cellular homeostasis.