Dynamic regulation of the Class II Transactivator (CIITA) through post translational modifications

Major histocompatibility class II (MHC II) molecules present extracellular antigens to CD4 + T cells and play vital roles in adaptive immune responses. Expression of MHC II is controlled at the level of transcription and requires binding of CIITA to the MHC II promoter. CIITA is also highly regulated, both at the level of transcription and post translational modification. We have previously linked activation of CIITA to monoubiquitination (Mono Ub) on degron proximal lysine residues and have shown CIITA Mono Ub to be dependent on prior phosphorylation. Mono Ub has opposing effects on CIITA as Mono Ub CIITA is initially targeted to the MHC II promoter to drive MHC II expression and, following promoter binding, Mono Ub CIITA is polyubiquitinated and degraded by the 26S proteasome. We have recently linked Sug1, a 19S proteasomal ATPase, to MHC II promoter recruitment of CIITA. We now identify the kinase ERK 1/2 as responsible for CIITA phosphorylation at degron localized serine 280. We further show that ERK 1/2 increases both CIITA ubiquitination and the interaction between Sug1 and CIITA. Together, these findings indicate a balance between CIITA activation and degradation that is mediated through regulated binding of CIITA to components of the proteasome. Importantly, our study provides insight into posttranslational codes that regulate protein activation and degradation. Research supported by grants from the American Cancer Society, the Georgia Cancer Coalition, and the Georgia Research Alliance (to S.F. Greer).