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

Abstract
Data availability
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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

1. Collins MA
2. et al
(2022) Variation in ubiquitin system genes creates substrate-specific effects on proteasomal protein degradation
NCBI Gene Expression Omnibus, GSE213689.

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE213689
1. Collins MA
2. et al
(2022) Variation in ubiquitin system genes creates substrate-specific effects on proteasomal protein degradation
Bioproject, PRJNA881749.

https://www.ncbi.nlm.nih.gov/bioproject?term=PRJNA881749

Article and author information

Author details

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.

"This ORCID iD identifies the author of this article:" 0000-0001-6799-5645
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.
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.

"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.

Copyright

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.