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

Area of Science:

• Cellular Biology
• Molecular Biology
• Protein Homeostasis

Background:

• The endoplasmic reticulum (ER) is crucial for protein folding and processing.
• Signal recognition particle (SRP) directs proteins to the ER via signal peptides.
• Cellular quality control mechanisms prevent accumulation of misfolded proteins.

Purpose of the Study:

• Identify key components of the regulation of aberrant protein production (RAPP) pathway.
• Elucidate the role of zinc finger antiviral protein (ZAP) in RAPP.
• Understand ZAP's mechanism in maintaining cellular homeostasis.

Main Methods:

• Functional genetic screens to identify RAPP pathway components.
• Proteomics and enhanced UV-crosslinking and immunoprecipitation (eCLIP) experiments.
• Investigating the interaction of ZAP-S with SRP and mRNA degradation.

Main Results:

• Zinc finger antiviral protein (ZAP) identified as a key RAPP pathway component.
• The ZAP-short isoform (ZAP-S) associates with SRP components.
• ZAP-S facilitates the degradation of aberrant mRNAs by recognizing faulty proteins early in biogenesis.

Conclusions:

• ZAP plays a critical role in safeguarding protein targeting to the ER.
• ZAP-S mediates mRNA degradation of aberrant proteins, preventing cellular stress.
• Loss of ZAP function triggers unfolded protein and integrated stress responses, impacting cellular homeostasis.