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Published on: August 13, 2013
Neddylation-CRLs regulate the functions of Treg immune cells
1Cancer Institute of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Abstract:
Neddylation, a ubiquitylation-like post-translational modification, is catalyzed by a cascade composed of three enzymes: E1 activating enzyme, E2 conjugating enzyme, and E3 ligase with cullins as physiological substrates. Specifically, neddylation E2 UBE2M couples with E3 RBX1 to neddylate cullins 1-4, whereas neddylation E2 UBE2F couples with E3 RBX2/SAG to neddylate cullin 5, leading to activation of CRL1-4 (Cullin-RING ligases 1-4) and CRL5, respectively. While over-activation of the neddylation-CRLs axis occurs frequently in many human cancers, how neddylation-CRLs regulate the function of immune cells, particularly Treg cells was previously unknown. To this end, we recently performed Treg selective knockout of two neddylation E2s and two E3s, individually, driven by Foxp3-Cre, and found that while the Ube2f-Sag E2/E3 pair plays a minimal role, if any, the Ube2m-Rbx1 pair is essential for the maintenance of Treg functionality, since their deletion triggers robust inflammatory response with autoimmune phenotypes. Milder phenotype severity upon Treg KO of upstream Ube2m than that of downstream Rbx1 strongly suggested that Rbx1 regulates Treg function in a manner dependent and independent of neddylation.
Insights
The UBE2M-RBX1 neddylation pathway is crucial for regulatory T (Treg) cell function and preventing autoimmune disease. Disrupting this pathway in Treg cells leads to inflammation and autoimmune phenotypes.
Area of Science:
- Biochemistry
- Immunology
- Molecular Biology
Background:
- Neddylation is a post-translational modification essential for protein ubiquitylation.
- Cullin-RING ligases (CRLs) are key substrates in neddylation pathways.
- Dysregulation of neddylation-CRL axis is implicated in human cancers.
Purpose of the Study:
- Investigate the role of neddylation-CRL axis in regulatory T (Treg) cell function.
- Determine the specific neddylation E2/E3 enzyme pairs involved in Treg cell regulation.
Main Methods:
- Treg-selective knockout of neddylation E2 (UBE2M, UBE2F) and E3 (RBX1, SAG) enzymes using Foxp3-Cre.
- Analysis of inflammatory responses and autoimmune phenotypes in knockout models.
Main Results:
- The UBE2M-RBX1 pair is essential for Treg cell maintenance and function.
- Deletion of UBE2M or RBX1 in Treg cells triggers significant inflammatory responses and autoimmune phenotypes.
- The UBE2F-SAG pair appears to play a minimal role in Treg cell function.
Conclusions:
- The UBE2M-RBX1 neddylation pathway is critical for Treg cell homeostasis.
- RBX1 regulates Treg function through both neddylation-dependent and independent mechanisms.
- Targeting the neddylation-CRL axis in Treg cells offers potential therapeutic strategies for autoimmune diseases.
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