Neddylation-CRLs regulate the functions of Treg immune cells

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.

Automated summary

Neddylation, a ubiquitylation-like post-translational modification, is essential for the maintenance of Treg functionality. The Ube2m-Rbx1 pair of neddylation enzymes plays a crucial role, while the Ube2f-Sag pair has minimal or no effect on Treg cells. Understanding the regulation of neddylation-CRLs axis in immune cells can provide insights into potential therapeutic targets for human cancers and autoimmune diseases.