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Aggregation of CAT tails blocks their degradation and causes proteotoxicity in S. cerevisiae

Cole S. Sitron, Joseph H. Park, Jenna M. Giafaglione, View ORCID ProfileOnn Brandman
doi: https://doi.org/10.1101/687319
Cole S. Sitron
1Department of Biochemistry, Stanford University, Stanford CA, 94305
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Joseph H. Park
1Department of Biochemistry, Stanford University, Stanford CA, 94305
2Department of Chemical & Systems Biology, Stanford University, Stanford CA, 94305
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Jenna M. Giafaglione
1Department of Biochemistry, Stanford University, Stanford CA, 94305
3Molecular Biology Interdepartmental Program, University of California Los Angeles, Los Angeles CA, 90095
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Onn Brandman
1Department of Biochemistry, Stanford University, Stanford CA, 94305
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  • ORCID record for Onn Brandman
  • For correspondence: onn@stanford.edu
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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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted September 17, 2019.
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Aggregation of CAT tails blocks their degradation and causes proteotoxicity in S. cerevisiae
Cole S. Sitron, Joseph H. Park, Jenna M. Giafaglione, Onn Brandman
bioRxiv 687319; doi: https://doi.org/10.1101/687319
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Aggregation of CAT tails blocks their degradation and causes proteotoxicity in S. cerevisiae
Cole S. Sitron, Joseph H. Park, Jenna M. Giafaglione, Onn Brandman
bioRxiv 687319; doi: https://doi.org/10.1101/687319

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