Ccr4-Not complex subunits Ccr4, Caf1, and Not4 are novel proteolysis factors promoting the degradation of ubiquitin-dependent substrates by the 26S proteasome
Copyright © 2021 Elsevier B.V. All rights reserved..
Degradation of short-lived and abnormal proteins is essential for normal cellular homeostasis. In eukaryotes, such unstable cellular proteins are selectively degraded by the ubiquitin proteasome system (UPS). Abnormalities in protein degradation by the UPS have been linked to several human diseases. Ccr4, Caf1, and Not4 proteins are known components of the Ccr4-Not multimeric complex. Ccr4 and Caf1 have established roles in transcription, mRNA de-adenylation and RNA degradation etc., while Not4 was shown to have important roles in regulating translation and protein quality control pathways. Here we show that Ccr4, Caf1, and Not4 have a novel function at a post-ubiquitylation step in the UPS pathway by promoting ubiquitin-dependent degradation of short-lived proteins by the 26S proteasome. Using a substrate of the well-studied ubiquitin fusion degradation (UFD) pathway, we found that its UPS-mediated degradation was severely impaired upon deletion of CCR4, CAF1, or NOT4 genes in Saccharomyces cerevisiae. Additionally, we show that Ccr4, Caf1, and Not4 bind to cellular ubiquitin conjugates, and that Ccr4 and Caf1 proteins interact with the proteasome. In contrast to Ccr4, Caf1, and Not4, other subunits of the Ccr4-Not complex are dispensable for UFD substrate degradation. From our findings we conclude that the Ccr4-Not complex subunits Ccr4, Caf1, and Not4 have a novel function outside of the canonical Ccr4-Not complex as a factor targeting ubiquitylated substrates for proteasomal degradation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:1868 |
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| Enthalten in: |
Biochimica et biophysica acta. Molecular cell research - 1868(2021), 6 vom: 22. Mai, Seite 119010 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kandasamy, Ganapathi [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.09.2021 Date Revised 16.09.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bbamcr.2021.119010 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM322836735 |
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| 100 | 1 | |a Kandasamy, Ganapathi |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Ccr4-Not complex subunits Ccr4, Caf1, and Not4 are novel proteolysis factors promoting the degradation of ubiquitin-dependent substrates by the 26S proteasome |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 16.09.2021 | ||
| 500 | |a Date Revised 16.09.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 Elsevier B.V. All rights reserved. | ||
| 520 | |a Degradation of short-lived and abnormal proteins is essential for normal cellular homeostasis. In eukaryotes, such unstable cellular proteins are selectively degraded by the ubiquitin proteasome system (UPS). Abnormalities in protein degradation by the UPS have been linked to several human diseases. Ccr4, Caf1, and Not4 proteins are known components of the Ccr4-Not multimeric complex. Ccr4 and Caf1 have established roles in transcription, mRNA de-adenylation and RNA degradation etc., while Not4 was shown to have important roles in regulating translation and protein quality control pathways. Here we show that Ccr4, Caf1, and Not4 have a novel function at a post-ubiquitylation step in the UPS pathway by promoting ubiquitin-dependent degradation of short-lived proteins by the 26S proteasome. Using a substrate of the well-studied ubiquitin fusion degradation (UFD) pathway, we found that its UPS-mediated degradation was severely impaired upon deletion of CCR4, CAF1, or NOT4 genes in Saccharomyces cerevisiae. Additionally, we show that Ccr4, Caf1, and Not4 bind to cellular ubiquitin conjugates, and that Ccr4 and Caf1 proteins interact with the proteasome. In contrast to Ccr4, Caf1, and Not4, other subunits of the Ccr4-Not complex are dispensable for UFD substrate degradation. From our findings we conclude that the Ccr4-Not complex subunits Ccr4, Caf1, and Not4 have a novel function outside of the canonical Ccr4-Not complex as a factor targeting ubiquitylated substrates for proteasomal degradation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Caf1 | |
| 650 | 4 | |a Ccr4-Not complex | |
| 650 | 4 | |a N-end rule pathway | |
| 650 | 4 | |a Not4 | |
| 650 | 4 | |a Ubiquitin fusion degradation (UFD) | |
| 650 | 7 | |a Repressor Proteins |2 NLM | |
| 650 | 7 | |a Saccharomyces cerevisiae Proteins |2 NLM | |
| 650 | 7 | |a Ubiquitin |2 NLM | |
| 650 | 7 | |a MOT2 protein, S cerevisiae |2 NLM | |
| 650 | 7 | |a EC 2.3.2.27 |2 NLM | |
| 650 | 7 | |a Ubiquitin-Protein Ligases |2 NLM | |
| 650 | 7 | |a EC 2.3.2.27 |2 NLM | |
| 650 | 7 | |a CCR4 protein, S cerevisiae |2 NLM | |
| 650 | 7 | |a EC 3.1.- |2 NLM | |
| 650 | 7 | |a Ribonucleases |2 NLM | |
| 650 | 7 | |a EC 3.1.- |2 NLM | |
| 650 | 7 | |a POP2 protein, S cerevisiae |2 NLM | |
| 650 | 7 | |a EC 3.1.13.4 |2 NLM | |
| 650 | 7 | |a Proteasome Endopeptidase Complex |2 NLM | |
| 650 | 7 | |a EC 3.4.25.1 |2 NLM | |
| 650 | 7 | |a ATP dependent 26S protease |2 NLM | |
| 650 | 7 | |a EC 3.4.99.- |2 NLM | |
| 700 | 1 | |a Pradhan, Ashis Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Palanimurugan, R |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Biochimica et biophysica acta. Molecular cell research |d 2017 |g 1868(2021), 6 vom: 22. Mai, Seite 119010 |w (DE-627)NLM264216326 |x 1879-2596 |7 nnns |
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