Formyl-methionine-mediated eukaryotic ribosome quality control pathway for cold adaptation

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Protein synthesis in eukaryotes initiates with methionine (Met) or formyl-methionine (fMet).
• Mechanisms for regulating fMet incorporation and preventing toxicity from fMet-bearing polypeptides are largely unknown.
• N-terminal fMet can lead to cellular toxicity if not properly managed during translation.

Purpose of the Study:

• To elucidate the mechanism for detecting and regulating fMet incorporation during eukaryotic translation.
• To identify the pathway responsible for preventing cellular toxicity associated with fMet-bearing polypeptides.
• To investigate the role of this pathway in yeast adaptation to stress conditions.

Main Methods:

• Described the fMet-mediated ribosome quality control (fMet-RQC) pathway in Saccharomyces cerevisiae.
• Identified Nip1 (eukaryotic translation initiation factor 3 subunit c) as a specific N-terminal fMet sensor.
• Demonstrated recruitment of Arf1 (small GTPase) to induce ribosome stalling and dissociation.

Main Results:

• Nip1 recognizes N-terminal fMet, recruiting Arf1 to stall ribosomes with fMet-peptidyl tRNAs.
• The fMet-RQC pathway leads to ribosome dissociation and stress granule formation.
• Loss of fMet-RQC results in continued synthesis of toxic fMet polypeptides, inhibiting Met modifications and causing coaggregation with ribosomes.

Conclusions:

• The fMet-RQC pathway is crucial for preventing cellular toxicity from aberrant fMet-initiated protein synthesis.
• This pathway is important for yeast adaptation to cold stress by promoting stress granule formation.
• fMet-RQC ensures proper protein synthesis regulation and prevents the accumulation of harmful fMet-polypeptides.