HYPOTHESIS AND THEORY article
Front. Immunol.
Sec. T Cell Biology
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1625419
This article is part of the Research TopicThe Role of Ubiquitin Ligases in Regulating Immune Cell Functions: Cbl and BeyondView all 4 articles
The Role of Ubiquitin Ligases in Regulating Immune Cell Functions
Provisionally accepted
- Department of Medicine, Stanford University, Stanford, CA, United States
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Regulatory T cells (Tregs) play a central role in immune homeostasis and the preservation of immunological self-tolerance. Treg activity depends on prolonged IL-2 receptor (IL-2R) signaling, and impairment or loss of this function has been linked to the development of autoimmune diseases. This review evaluates the hypothesis that disrupted IL-2R signaling, due to enhanced desensitization, impairs Treg suppressive function and contributes to autoimmunity. In mice and humans, desensitization of IL-2R signaling by the cullin-RING ligase 5 (CRL5) complex leads to reduced persistence of phosphorylated JAK1 (pJAK1) and its downstream effector pSTAT5, a transcription factor critical for Treg function. Activation of CRL5 requires neddylation—a post-translational modification in which the ubiquitin-like NEDD8 is conjugated to lysine 724 on cullin-5 (CUL5), the scaffold protein of CRL5. Neddylation permits untethering of the RING-box protein RBX, enabling E2 enzyme-mediated ubiquitination and proteasomal degradation of pJAK1 via recruitment by suppressor of cytokine signaling 3 (SOCS3). This process, known as IL-2R signal desensitization, is antagonized in Tregs by the E3 ligase GRAIL (Gene Related to Anergy in Lymphocytes, RNF128), which mono-ubiquitinates Lys724 to block neddylation, preventing CRL5 activation and pJAK1 degradation. An imbalance between neddylation and mono-ubiquitination at Lys724 compromises IL-2R signaling and promotes autoimmune pathology, and studies show GRAIL expression is diminished in Tregs from autoimmune patients and mouse models, leading to reduced pSTAT5 activity and impaired suppressive capacity. Pharmacologic inhibition of neddylation with pathway inhibitors (NAEi) restores IL-2R signaling and Treg function, highlighting the therapeutic potential of targeting this regulatory axis to preserve immune tolerance.
Keywords: Neddylation, Regulatory T cell (Treg), cullin ring ligases (CRLs), IL-2 receptorsignaling, pJAK1 degradation, GRAIL, neddylation activating enzyme inhibitor (NAEi)
Received: 08 May 2025; Accepted: 30 Sep 2025.
Copyright: © 2025 Marty, Yip, Wang, Kumar and Fathman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: C Garrison Fathman, cfathman@stanford.edu
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.