The Functional Redundancy of Neddylation E2s and E3s in Modulating the Fitness of Regulatory T Cells.

Neddylation is necessary for activation of Cullin-RING ligases (CRLs), which degrade various immune regulatory proteins. Our recent study showed that while depletion of neddylation E2-E3 pair Ube2f-Sag in regulatory T (T reg ) cells had no obvious phenotype, the same depletion of either Ube2m or Rbx1 caused inflammation disorders with different severity. Whether these E2s or E3s compensate each other in functional regulations of T reg cells is, however, previously unknown. In this report, we generated Foxp3 Cre ; Ube2m fl / fl ; Ube2f fl / fl or Foxp3 Cre ; Rbx1 fl / fl ; Sag fl / fl double-null mice by simultaneous deletion of both neddylation E2s or E3s in T reg cells, respectively. Remarkably, Ube2m&Ube2f double-null mice developed much severe autoimmune phenotypes than did Ube2m -null mice, indicating that Ube2m markedly compensates Ube2f in T reg cells. The minor worsened autoimmune phenotypes seen at the very early stage in Rbx1&Sag double-null than Rbx1 -null mice is likely due to already severe phenotypes of the later, indicating a minor compensation of Rbx1 for Sag . The RNA profiling-based analyses revealed that up- and down-regulations of few signaling pathways in T reg cells are associated with the severity of autoimmune phenotypes. Finally, severer inflammation phenotypes seen in mice with double E3-null than with double E2-null T reg cells indicate a neddylation-independent mechanism of 2 E3s, also known to serve as the RING component of CRLs in regulation of T reg cell fitness.