内丁酰化是一种类似泛素化的翻译后修饰，由三种酶级联催化：E1激活酶、E2结合酶以及E3连接酶，其中cullin是其生理底物。具体来说，内丁酰化E2 UBE2M与E3 RBX1配对内丁酰化cullin 1-4，而内丁酰化E2 UBE2F与E3 RBX2/SAG配对内丁酰化cullin 5，从而激活CRL1-4（cullin-RING ligases 1-4）和CRL5。虽然内丁酰化-CRLs轴的过度激活在许多人类癌症中经常发生，但内丁酰化-CRLs如何调节免疫细胞的功能，特别是调节性T细胞，以前尚不清楚。为此，我们最近通过Foxp3-Cre驱动实现转录因子Foxp3选择性敲除了两种内丁酰化E2和两种E3，分别发现Ube2f-Sag E2/E3配对在Treg中发挥最小的作用（如果有的话），而Ube2m-Rbx1配对对于Treg功能的维持是至关重要的，因为它们的敲除会触发强烈的炎症反应和自身免疫表型。 Treg在上游Ube2m KO的轻微表型严重程度比下游Rbx1 KO进一步说明，Rbx1以依赖和独立于内丁酰化的方式调节Treg功能。© 2023 Wiley Periodicals LLC.

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.© 2023 Wiley Periodicals LLC.