Variation in ubiquitin system genes creates substrate-specific effects on proteasomal protein degradation

  1. Mahlon A Collins  Is a corresponding author
  2. Gemechu Mekonnen
  3. Frank Wolfgang Albert  Is a corresponding author
  1. University of Minnesota, United States

Abstract

Precise control of protein degradation is critical for life, yet how natural genetic variation affects this essential process is largely unknown. Here, we developed a statistically powerful mapping approach to characterize how genetic variation affects protein degradation by the ubiquitin-proteasome system (UPS). Using the yeast Saccharomyces cerevisiae, we systematically mapped genetic influences on the N-end rule, a UPS pathway in which protein N-terminal amino acids function as degradation-promoting signals. Across all 20 possible N-terminal amino acids, we identified 149 genomic loci that influence UPS activity, many of which had pathway- or substrate-specific effects. Fine-mapping of four loci identified multiple causal variants in each of four ubiquitin system genes whose products process (NTA1), recognize (UBR1 and DOA10), and ubiquitinate (UBC6) cellular proteins. A cis-acting promoter variant that modulates UPS activity by altering UBR1 expression alters the abundance of 36 proteins without affecting levels of the corresponding mRNAs. Our results reveal a complex genetic basis of variation in UPS activity.

Data availability

Raw sequencing reads from QTL mapping experiments are available from the NIH Sequence Read Archive under the Bioproject Accession PRJNA881749. Raw and processed RNA-seq data is available from the NIH Gene Expression Omnibus under the accession GSE213689. These datasets are fully available without restriction.Computational scripts used to process data, for statistical analysis, and to generate figures are available at: https://www.github.com/mac230/N-end_Rule_QTL_paper

The following data sets were generated

Article and author information

Author details

  1. Mahlon A Collins

    Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, United States
    For correspondence
    mahlon@umn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6799-5645
  2. Gemechu Mekonnen

    Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Frank Wolfgang Albert

    Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, United States
    For correspondence
    falbert@umn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1380-8063

Funding

National Institutes of Health (F32-GM128302)

  • Mahlon A Collins

National Institutes of Health (R35-GM124676)

  • Frank Wolfgang Albert

Pew Charitable Trusts (Scholarship in the Biomedical Sciences)

  • Frank Wolfgang Albert

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Magnus Nordborg, Gregor Mendel Institute, Austria

Version history

  1. Preprint posted: May 6, 2021 (view preprint)
  2. Received: April 19, 2022
  3. Accepted: October 10, 2022
  4. Accepted Manuscript published: October 11, 2022 (version 1)
  5. Version of Record published: November 2, 2022 (version 2)

Copyright

© 2022, Collins et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Mahlon A Collins
  2. Gemechu Mekonnen
  3. Frank Wolfgang Albert
(2022)
Variation in ubiquitin system genes creates substrate-specific effects on proteasomal protein degradation
eLife 11:e79570.
https://doi.org/10.7554/eLife.79570

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https://doi.org/10.7554/eLife.79570

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