The Ribosome-associated Quality Control (RQC) pathway targets incomplete polypeptides from stalled translation for degradation. The primary route of degradation involves ubiquitylation of ribosome-tethered incomplete polypeptides by the E3 ligase Ltn1. To safeguard cells from Ltn1 failure, the protein Rqc2 directs the ribosome to append incomplete polypeptides with carboxy-terminal alanine and threonine residues (CAT tails) that act as degrons, marking RQC-evading polypeptides for degradation.

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... tn1 disruption leads to neurodegeneration in animal models yet how this becomes toxic to cells is unclear. We show here that increased Rqc2 levels alter CAT tail composition and exacerbate the toxicity of Ltn1 failure by driving CAT tail aggregation, which inhibits CAT tail degron activity and disrupts proteostasis. Guanidinium hydrochloride exposure or RNA Polymerase III perturbation reverses these Rqc2-induced effects. Our work demonstrates that increased Rqc2 levels convert CAT tails from degrons into toxic aggregates and that pharmacologic or genetic interventions can reverse this process.