The Class II Transactivator (CIITA) is an important transcription factor of Major Histocompatibility II (MHC II) genes. Defects in CIITA, as occur in Bare Lymphocyte Syndrome, lead to the loss of MHC II expression and subsequent inability to activate an immune response. Accordingly, CIITA has often been termed the master switch of the immune system. Its underactivation results in immunodeficiencies whereas its overactivation may lead to autoimmune disorders. Therefore, the activity of CIITA must be tightly regulated through multiple post translational modifications, including phosphorylation and ubiquitination, to ensure proper levels of activation.<br/>We identified a sequence within CIITA from amino acids 283 to 289 that matches a consensus 14-3-3 binding site motif: RxxxpTxP and decided to explore the effects of the 14-3-3β isoform on CIITA. We have shown through immunoprecipitations that CIITA interacts with 14-3-3β and that this interaction leads to the proteasome mediated degradation of CIITA. Mutating the binding site results in hindered stereochemical interactions between the two proteins, leading to increased stability of mutants as compared to wild type CIITA. Additionally, phosphorylation at the threonine residue in this binding site is necessary for the interaction and effects of 14-3-3β upon CIITA.<br/>We have shown that 14-3-3β leads to the degradation of CIITA by scaffolding it to a cellular factor and altering its stability. Much work remains to be done to determine what this cellular factor is and the changes in transactivation potential of CIITA as a result of 14-3-3β interaction.

Regulation of the class II transactivator (CIITA) by the molecular scaffold 14-3-3 beta

255th National Meeting (2018)

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