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Open AccessArticle

The Arg/N-Degron Pathway—A Potential Running Back in Fine-Tuning the Inflammatory Response?

1
Skolkovo Institute of Science and Technology, 121205 Moscow, Russia
2
Institute of Mathematical Problems of Biology, Keldysh Institute of Applied Mathematics, Russian Academy of Sciences, Pushchino, 142290 Moscow, Russia
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(6), 903; https://doi.org/10.3390/biom10060903
Received: 12 May 2020 / Revised: 9 June 2020 / Accepted: 12 June 2020 / Published: 14 June 2020
(This article belongs to the Special Issue Looking Back and Ahead: Emerging Concepts in Ubiquitin and UBLs)
Recognition of danger signals by a cell initiates a powerful cascade of events generally leading to inflammation. Inflammatory caspases and several other proteases become activated and subsequently cleave their target proinflammatory mediators. The irreversible nature of this process implies that the newly generated proinflammatory fragments need to be sequestered, inhibited, or degraded in order to cancel the proinflammatory program or prevent chronic inflammation. The Arg/N-degron pathway is a ubiquitin-dependent proteolytic pathway that specifically degrades protein fragments bearing N-degrons, or destabilizing residues, which are recognized by the E3 ligases of the pathway. Here, we report that the Arg/N-degron pathway selectively degrades a number of proinflammatory fragments, including some activated inflammatory caspases, contributing in tuning inflammatory processes. Partial ablation of the Arg/N-degron pathway greatly increases IL-1β secretion, indicating the importance of this ubiquitous pathway in the initiation and resolution of inflammation. Thus, we propose a model wherein the Arg/N-degron pathway participates in the control of inflammation in two ways: in the generation of inflammatory signals by the degradation of inhibitory anti-inflammatory domains and as an “off switch” for inflammatory responses through the selective degradation of proinflammatory fragments. View Full-Text
Keywords: Arg/N-degron pathway; UBR-ubiquitin ligases; ubiquitin; proteolysis; inflammatory caspases; inflammation Arg/N-degron pathway; UBR-ubiquitin ligases; ubiquitin; proteolysis; inflammatory caspases; inflammation
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Leboeuf, D.; Pyatkov, M.; Zatsepin, T.S.; Piatkov, K. The Arg/N-Degron Pathway—A Potential Running Back in Fine-Tuning the Inflammatory Response? Biomolecules 2020, 10, 903.

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