Requirement of Rbx1 Cullin-Ring ligase E3 and Ube2m neddylation E2 in the maintenance of the fitness of Treg cells
Cullin-RING Ligases (CRLs), upon activation by neddylation, play key roles in many biological processes. However, how CRL-neddylation regulates the function of Treg cells remains elusive. Here we show that mice with Treg-specific deletion of Rbx1, a RING component of CRLs required for its activity, developed an early-onset fetal inflammatory disorders and death at day ~25 after birth with disrupted homeostasis and impaired functions of Treg cells. Specifically, Rbx1 is essential for maintenance of the effector subpopulations in Treg cells, and regulates several inflammatory pathways. Similar phenotypes were seen in mice with deletion of Ube2m, a neddylation E2, in Treg cells, but with much lesser severity. Our study shows that the Ube2m-Rbx1 axis is required for the maintenance of homeostasis and functional fitness of Treg cells; also uncovers Ube2m-independent roles of Rbx1 in Treg cells, suggesting a layer of complexity in control of CRLs E3 ligases that is not fully understood.