Abstract
The Ribosome-associated Quality Control (RQC) pathway co-translationally marks incomplete polypeptides from stalled translation with two signals that trigger their proteasome-mediated degradation. The E3 ligase Ltn1 adds ubiquitin and Rqc2 directs the large ribosomal subunit to append carboxy-terminal alanine and threonine residues (CAT tails). When excessive amounts of incomplete polypeptides evade Ltn1, CAT-tailed proteins accumulate and can self-associate into aggregates. CAT tail aggregation has been hypothesized to either protect cells by sequestering potentially toxic incomplete polypeptides or harm cells by disrupting protein homeostasis. To distinguish between these possibilities, we modulated CAT tail aggregation in Saccharomyces cerevisiae with genetic and chemical tools to analyze CAT tails in aggregated and un-aggregated states. We found that enhancing CAT tail aggregation induces proteotoxic stress and antagonizes degradation of CAT-tailed proteins, while inhibiting aggregation reverses these effects. Our findings suggest that CAT tail aggregation harms RQC-compromised cells and that preventing aggregation can mitigate this toxicity.
Highlights
Failed rounds of translation produce incomplete, potentially toxic polypeptides that organisms across all clades of life have evolved responses to degrade [1,2,3,4,5]
RQCsub consists of green fluorescent protein (GFP) attached via an inert linker including a tobacco etch virus (TEV) protease site to twelve stall-inducing arginine CGN codons (Fig 1A) [42]
This result indicates that Rqc2 and Ltn1 contribute to RQCsub degradation
Summary
Failed rounds of translation produce incomplete, potentially toxic polypeptides that organisms across all clades of life have evolved responses to degrade [1,2,3,4,5]. The tmRNA enters stalled ribosomes, re-initiates translation elongation with its tRNA moiety and switches the ribosome’s template to its mRNA moiety [1] This prompts the ribosome to synthesize a tmRNA-encoded tag on the incomplete polypeptide’s C-terminus that marks it for proteolysis [1]. The eukaryotic response, called Ribosome-associated Quality Control (RQC), begins when a set of factors recognize ribosomes that have stalled on the same mRNA and collided into each other [6,7,8]. These factors split the ribosomes into their large and small
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