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

Mahlon A Collins; Gemechu Mekonnen; Frank Wolfgang Albert

doi:10.7554/eLife.79570

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

Mahlon A Collins, Gemechu Mekonnen, Frank Wolfgang Albert

Genetics, Cell Biology and Development (CBS)

Research output: Contribution to journal › Article › peer-review

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 mRNA transcripts. Our results reveal a complex genetic basis of variation in UPS activity.

Original language	English (US)
Article number	e79570
Journal	eLife
Volume	11
DOIs	https://doi.org/10.7554/eLife.79570
State	Published - Oct 2022

Bibliographical note

Funding Information:
We thank Leonid Kruglyak for the BY and RM yeast strains and Michael Knop for technical assistance in implementing the TFT reporter system. We thank the University of Minnesota’s Flow Cytometry Resource, Genomics Center, and Center for Mass Spectrometry and Proteomics for their contributions to the project. We thank Margaret Kliebhan for the BY / RM variant file used for QTL mapping. We thank the members of the Albert laboratory and the BioKansas Scientific Writing Program for critical feedback on the manuscript. This work was supported by NIH grants F32-GM128302 to MAC and R35-GM124676 to FWA, as well as a Pew Scholarship in the Biomedical Sciences from the Pew Charitable Trusts to FWA. 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.

Funding Information:
We thank Leonid Kruglyak for the BY and RM yeast strains and Michael Knop for technical assistance in implementing the TFT reporter system. We thank the University of Minnesota’s Flow Cytometry Resource, Genomics Center, and Center for Mass Spectrometry and Proteomics for their contributions to the project. We thank Margaret Kliebhan for the BY / RM variant file used for QTL mapping. We thank the members of the Albert laboratory and the BioKansas Scientific Writing Program for critical feedback on the manuscript. This work was supported by NIH grants F32-GM128302 to MAC and R35-GM124676 to FWA, as well as a Pew Scholarship in the Biomedical Sciences from the Pew Charitable Trusts to FWA.

Publisher Copyright:
© Collins et al.

PubMed: MeSH publication types

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Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

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@article{a244d92a6aca4084981a1938ee3965c5,

title = "Variation in ubiquitin system genes creates substrate-specific effects on proteasomal protein degradation",

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 mRNA transcripts. Our results reveal a complex genetic basis of variation in UPS activity.",

author = "Collins, {Mahlon A} and Gemechu Mekonnen and Albert, {Frank Wolfgang}",

note = "Funding Information: We thank Leonid Kruglyak for the BY and RM yeast strains and Michael Knop for technical assistance in implementing the TFT reporter system. We thank the University of Minnesota{\textquoteright}s Flow Cytometry Resource, Genomics Center, and Center for Mass Spectrometry and Proteomics for their contributions to the project. We thank Margaret Kliebhan for the BY / RM variant file used for QTL mapping. We thank the members of the Albert laboratory and the BioKansas Scientific Writing Program for critical feedback on the manuscript. This work was supported by NIH grants F32-GM128302 to MAC and R35-GM124676 to FWA, as well as a Pew Scholarship in the Biomedical Sciences from the Pew Charitable Trusts to FWA. 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. Funding Information: We thank Leonid Kruglyak for the BY and RM yeast strains and Michael Knop for technical assistance in implementing the TFT reporter system. We thank the University of Minnesota{\textquoteright}s Flow Cytometry Resource, Genomics Center, and Center for Mass Spectrometry and Proteomics for their contributions to the project. We thank Margaret Kliebhan for the BY / RM variant file used for QTL mapping. We thank the members of the Albert laboratory and the BioKansas Scientific Writing Program for critical feedback on the manuscript. This work was supported by NIH grants F32-GM128302 to MAC and R35-GM124676 to FWA, as well as a Pew Scholarship in the Biomedical Sciences from the Pew Charitable Trusts to FWA. Publisher Copyright: {\textcopyright} Collins et al.",

year = "2022",

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N1 - Funding Information: We thank Leonid Kruglyak for the BY and RM yeast strains and Michael Knop for technical assistance in implementing the TFT reporter system. We thank the University of Minnesota’s Flow Cytometry Resource, Genomics Center, and Center for Mass Spectrometry and Proteomics for their contributions to the project. We thank Margaret Kliebhan for the BY / RM variant file used for QTL mapping. We thank the members of the Albert laboratory and the BioKansas Scientific Writing Program for critical feedback on the manuscript. This work was supported by NIH grants F32-GM128302 to MAC and R35-GM124676 to FWA, as well as a Pew Scholarship in the Biomedical Sciences from the Pew Charitable Trusts to FWA. 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. Funding Information: We thank Leonid Kruglyak for the BY and RM yeast strains and Michael Knop for technical assistance in implementing the TFT reporter system. We thank the University of Minnesota’s Flow Cytometry Resource, Genomics Center, and Center for Mass Spectrometry and Proteomics for their contributions to the project. We thank Margaret Kliebhan for the BY / RM variant file used for QTL mapping. We thank the members of the Albert laboratory and the BioKansas Scientific Writing Program for critical feedback on the manuscript. This work was supported by NIH grants F32-GM128302 to MAC and R35-GM124676 to FWA, as well as a Pew Scholarship in the Biomedical Sciences from the Pew Charitable Trusts to FWA. Publisher Copyright: © Collins et al.

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N2 - 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 mRNA transcripts. Our results reveal a complex genetic basis of variation in UPS activity.

AB - 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 mRNA transcripts. Our results reveal a complex genetic basis of variation in UPS activity.

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

Abstract

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