Double deletion of neddylation E2s Ube2m&Ube2f or E3s Rbx1&Sag in Treg cells leads to the impairment of suppressive function of Treg cells and results in severe autoimmune disorders, fully demonstrating the pivotal role of the neddylation-CRL axis in the maintenance of Treg cell fitness. Here, UBE2F is linked to autoimmune disease.