Major histocompatibility class II (MHC class II) molecules are glycoproteins 
that present extracellular antigens to CD4(+) T cells and are essential for 
initiation of adaptive immune responses. MHC class II expression requires 
recruitment of a master regulator, the class II transactivator (CIITA), to the 
MHC class II promoter. Others and we have earlier linked CIITA to the 
ubiquitin-proteasome system by showing that mono-ubiquitination of CIITA 
increases its transactivity, whereas poly-ubiquitination of CIITA leads to its 
degradation. We have further shown that the 26S proteasome also has 
non-proteolytic functions in MHC class II transcription, as 19S ATPase subunits 
of the 26S proteasome positively regulate MHC class II transcription and are 
necessary for stable promoter binding of CIITA. Although these basic 
requirements of the proteasome to initiate MHC class II transcription are known, 
how CIITA is recruited, stabilized, and degraded remains unclear. Here, we 
identify a novel N-terminal 19S ATPase-binding domain of CIITA. The 
ATPase-binding domain lies within the proline/serine/threonine-rich region of 
CIITA and encompasses a majority of the CIITA degron sequence. Absence of the 
ATPase-binding domain increases the half-life of CIITA, but blocks MHC class II 
surface expression, indicating that CIITA requires interaction with the 19S 
ATPases for both appropriate deployment and destruction.