Association of the 19S proteasomal ATPases with the ATPase-binding domain of CIITA is essential for CIITA stability and MHC class II expression.
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.
Bhat
Kavita Purnanda
KP
Division of Cellular and Molecular Biology and Physiology, Department of Biology, Georgia State University, Atlanta, GA 30302, USA.
Truax
Agnieszka Dorota
AD
Brooks
Jeanne Kaye
JK
Greer
Susanna Fletcher
SF
D000074183:ATPases Associated with Diverse Cellular Activities; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D006367:HeLa Cells; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D060588:LIM Domain Proteins; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D055550:Protein Stability; D017434:Protein Structure, Tertiary / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000276:immunology; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; D000949:Histocompatibility Antigens Class II; D060588:LIM Domain Proteins; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; C092282:PSMC5 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities