The Ube2m-Rbx1 neddylation-Cullin-RING-Ligase proteins are essential for the maintenance of Regulatory T cell fitness

Absence of regulatory T cells results in a severe inflammatory disease which leads to death in infancy in both human patients and in mouse models. Authors show here that in mice, conditional deletion of Rbx1, the RING component of Cullin-RING ligases in regulatory T cells causes a similar phenotype, due to the disrupted degradation of important regulatory proteins. Neddylation-mediated activation of Cullin-RING E3 Ligases (CRLs) are necessary for the degradation of specific immune regulatory proteins. However, little is known about how these processes govern the function of regulatory T (Treg) cells. Here we show that mice with Treg cell-specific deletion of Rbx1, a dual E3 for both neddylation and ubiquitylation by CRLs, develop an early-onset fatal inflammatory disorder, characterized by disrupted Treg cell homeostasis and suppressive functions. Specifically, Rbx1 is essential for the maintenance of an effector Treg cell subpopulation, and regulates several inflammatory pathways. Similar but less severe phenotypes are observed in mice having Ube2m, a neddylation E2 conjugation enzyme, deleted in their Treg cells. Interestingly, Treg-specific deletion of Rbx2/Sag or Ube2f, components of a similar but distinct neddylation-CRL complex, yields no obvious phenotype. Thus, our work demonstrates that the Ube2m-Rbx1 axis is specifically required for intrinsic regulatory processes in Treg cells; and that Rbx1 might also play Ube2m-independent roles in maintaining the fitness of Treg cells, suggesting a layer of complexity in neddylation-dependent activation of CRLs.

Automated summary

This study reveals that the absence of Rbx1, a component of Cullin-RING ligases, in regulatory T cells leads to a severe inflammatory disease. The Ube2m-Rbx1 axis is specifically required for intrinsic regulatory processes in Treg cells.