ArticleProceedings of the National Academy of Sciences of the United States of America2020
The Arg/N-degron pathway targets transcription factors and regulates specific genes.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 18 citations in OpenAlex.
- A C-degron regulates Chk1 kinase by allowing stability of inactive Chk1 and by making it short- lived upon activation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Molecular Mechanisms and Therapeutic Potential of Degron-Mediated Proteostasis Regulation in Neurodegenerative Diseases.Cellular and molecular neurobiology · 2026Review
- An Enigma of N-termini dependent protein degradation.Biochemistry and biophysics reports · 2025Article
- Structure and Mechanism of Aminoacyl-tRNA-Protein L/F- and R-transferases.Journal of molecular biology · 2025Review
- Global profiling of N-terminal cysteine-dependent degradation mechanisms.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- SOD2 is a regulator of proteasomal degradation promoting an adaptive cellular starvation response.Cell reports · 2025Article
- Redox regulation: mechanisms, biology and therapeutic targets in diseases.Signal transduction and targeted therapy · 2025Review
- N-degron pathways.Proceedings of the National Academy of Sciences of the United States of America · 2024Review
- Non-standard amino acid incorporation into thiol dioxygenases.Methods in enzymology · 2024Article
- Stability dynamics of neurofilament and GFAP networks and protein fragments.Current opinion in cell biology · 2023Review
- The CRL3Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Crystal structure of the Ate1 arginyl-tRNA-protein transferase and arginylation of N-degron substrates.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Aminopeptidases trim Xaa-Pro proteins, initiating their degradation by the Pro/N-degron pathway.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Review
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Authors and funding
4 authors at 2 institutions in 1 country.
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Abstract
The Arg/N-degron pathway targets proteins for degradation by recognizing their N-terminal or internal degrons. Our previous work produced double-knockout (2-KO) HEK293T human cell lines that lacked the functionally overlapping UBR1 and UBR2 E3 ubiquitin ligases of the Arg/N-degron pathway. Here, we studied these cells in conjunction with RNA-sequencing, mass spectrometry (MS), and split-ubiquitin binding assays. 1) Some mRNAs, such as those encoding lactate transporter MCT2 and β-adrenergic receptor ADRB2, are strongly (∼20-fold) up-regulated in 2-KO cells, whereas other mRNAs, including those encoding MAGEA6 (a regulator of ubiquitin ligases) and LCP1 (an actin-binding protein), are completely repressed in 2-KO cells, in contrast to wild-type cells. 2) Glucocorticoid receptor (GR), an immunity-modulating transcription factor (TF), is up-regulated in 2-KO cells and also physically binds to UBR1, strongly suggesting that GR is a physiological substrate of the Arg/N-degron pathway. 3) PREP1, another TF, was also found to bind to UBR1. 4) MS-based analyses identified ∼160 proteins whose levels were increased or decreased by more than 2-fold in 2-KO cells. For example, the homeodomain TF DACH1 and the neurofilament subunits NF-L (NFEL) and NF-M (NFEM) were expressed in wild-type cells but were virtually absent in 2-KO cells. 5) The disappearance of some proteins in 2-KO cells took place despite up-regulation of their mRNAs, strongly suggesting that the Arg/N-degron pathway can also modulate translation of specific mRNAs. In sum, this multifunctional proteolytic system has emerged as a regulator of mammalian gene expression, in part through conditional targeting of TFs that include ATF3, GR, and PREP1.
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