Mechanical forces regulate the composition and fate of stalled nascent chains

Area of Science:

• Molecular Biology
• Protein Degradation Pathways
• Ribosome Function

Background:

• The ribosome-associated quality control (RQC) pathway manages stalled ribosomes.
• During RQC, stalled nascent chains (NCs) receive C-terminal amino acid tails (CAT tails) via non-canonical elongation.
• The functional role of CAT tail composition (alanine [Ala] and threonine [Thr] in yeast) was previously unknown.

Purpose of the Study:

• To investigate the relationship between CAT tail composition and function in yeast.
• To elucidate the regulatory mechanisms governing CAT tailing during ribosome-associated quality control.

Main Methods:

• Biochemical approaches in yeast.
• Analysis of mechanical forces regulating nascent chain modification.
• Investigation of CAT tail composition effects on protein processing.

Main Results:

• Mechanical forces on nascent chains regulate CAT tailing.
• CAT tailing operates in "extrusion mode" (Thr-rich) for ubiquitylation, then switches to "release mode" (Ala-only) for degradation.
• Threonine in CAT tails prevents polyalanine formation, enhancing extrusion and termination.
• Failure to switch modes causes NC accumulation and proteotoxic aggregation.

Conclusions:

• Mechanical forces are key regulators of CAT tailing.
• CAT tail composition dynamically controls nascent chain processing and degradation.
• Dysregulation of CAT tailing leads to proteotoxicity.