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CIITA and Its Dual Roles in MHC Gene Transcription

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CIITA and Its Dual Roles in MHC Gene Transcription REVIEW ARTICLE published: 20 December 2013 doi: 10.3389/fimmu.2013.00476 CIITA and its dual roles in MHC gene transcription Ballachanda N. Devaiah and Dinah S. Singer* Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD, USA Edited by: Class II transactivator (CIITA) is a transcriptional coactivator that regulates g-interferon- Ananda L. Roy, Tufts University School activated transcription of Major Histocompatibility Complex (MHC) class I and II genes. As of Medicine, USA such, it plays a critical role in immune responses: CIITA deficiency results in aberrant MHC Reviewed by: John D. Colgan, The University of gene expression and consequently in autoimmune diseases such as Type II bare lympho- Iowa, USA cyte syndrome. Although CIITA does not bind DNA directly, it regulates MHC transcription Barbara Nikolajczyk, Boston in two distinct ways – as a transcriptional activator and as a general transcription factor. As University School of Medicine, USA an activator, CIITA nucleates an enhanceosome consisting of the DNA binding transcription *Correspondence: factors RFX, cyclic AMP response element binding protein, and NF-Y. As a general tran- Dinah S. Singer, Experimental Immunology Branch, National Cancer scription factor, CIITA functionally replaces the TFIID component, TAF1. Like TAF1, CIITA Institute, NIH, 9000 Rockville Pike, possesses acetyltransferase (AT) and kinase activities, both of which contribute to proper Building 10, Room 4B36, Bethesda, transcription of MHC class I and II genes. The substrate specificity and regulation of the MD 20892, USA CIITA AT and kinase activities also parallel those of TAF1. In addition, CIITA is tightly reg- e-mail: [email protected] ulated by its various regulatory domains that undergo phosphorylation and influence its targeted localization.Thus, a complex picture of the mechanisms regulating CIITA function is emerging suggesting that CIITA has dual roles in transcriptional regulation which are summarized in this review. Keywords: CIITA, MHC transcription, NLR/CATERPILLER proteins, enhanceosome, TAF1, general transcription factors The class II transactivator (CIITA) is a master regulator of major expression has been correlated with a variety of diseases (11). Of histocompatibility complex (MHC) gene expression. It induces de these, only CIITA is a critical mediator of adaptive immunity. Con- novo transcription of MHC class II genes and enhances constitu- stitutive expression of CIITA is limited to antigen presenting cells. tive MHC class I gene expression. The role of CIITA in regulating However, g-interferon exposure induces de novo CIITA expression MHC gene transcription is well established: CIITA deficiency or in most cell types (12, 13). Its activity is known to be modulated aberrant expression is linked to the Type II bare lymphocyte syn- by several posttranslational modifications including phosphory- drome and to cancer, respectively (1, 2). Although CIITA has been lation, ubiquitination, acetylation, and deacetylation (14). CIITA primarily characterized as a transcriptional regulator of MHC can also self-associate and oligomerize (15, 16). CIITA activity genes, it also regulates transcription of over 60 immunologi- is further modulated by its cellular localization: the GTP bind- cally important genes, including interleukin 4 (IL-4), IL-10, and ing domain (GBD) of CIITA regulates its shuttling between the a variety of thyroid-specific genes (3, 4). Despite the important nucleus and cytoplasm (17, 18). role of CIITA in regulating expression of these genes, the actual Class II transactivator consists of a series of regulatory domains mechanisms by which it functions are still being unraveled. Early that include an activation domain (AD), an acetyltransferase (AT) studies established that CIITA is a coactivator that nucleates the domain, a proline/serine/threonine (PST) domain, a GBD and formation of an enhanceosome with transcription factors bind- finally, the canonical LRR domain common to all NLR proteins. ing to enhancer elements in the upstream regions of the MHC The CIITA AD domain binds to general transcription factors and genes (5, 6). In addition, more recent studies from our lab have the CREB-binding protein (CBP), leading to activation of the demonstrated that it also functions as a component of the basal MHC class II promoter and repression of the IL-4 promoter (19, transcriptional machinery (7–9). Here we review the two dis- 20). This domain also partially overlaps the region required for the tinct mechanisms by which CIITA regulates transcription of MHC AT activity of CIITA (7). The role of the PST domain, which while class I and II genes and speculate on how these activities may be essential for CIITA function, remains unknown (21). The LRR interconnected. domain, which interacts with the GBD, is known to play an impor- tant role in CIITA movement into the nucleus and in regulating CIITA BELONGS TO THE FAMILY OF NLR/CATERPILLER its transactivation function (15, 21, 22). The GBD domain, which PROTEINS is perhaps the best studied among the CIITA domains, has been The members of the NLR/CATERPILLER family of proteins are shown to be the site of interaction of several DNA binding transac- defined by their structures which include both a nucleotide bind- tivators (23). The GBD regulates translocation of CIITA: mutation ing domain (NBD) and a C-terminal leucine rich region (LRR) or deletion of the GBD results in increased nuclear export, suggest- (10). Of the nearly two dozen genes within the family,many encode ing that it is a negative regulator of CIITA nuclear export (18). Two proteins that mediate inflammatory responses and whose aberrant nuclear localization signals have been mapped to the N-terminal www.frontiersin.org December 2013 | Volume 4 | Article 476 | 1 Devaiah and Singer The dual roles of CIITA domain, as well as an additional one in the C-terminus (18). CIITA The concept of a CIITA-nucleated enhanceosome fits well also contains two LxxLL motifs which are crucial for the transacti- with the regulation of MHC class I and II transcription, and vation function and self-association of CIITA (24). In addition to is supported by considerable circumstantial evidence. Such evi- these multifunctional domains, CIITA also contains two degrons dence includes the demonstration of direct interaction between in the AD and PST domains respectively. These degrons signal the CIITA and the other components of the predicted enhanceo- rapid degradation of CIITA through the ubiquitin-proteasome some (5). However, CIITA also transactivates many genes that pathway, and are responsible for the instability and short half- may not possess the cis-elements and trans-factors that are found life of CIITA (~30 min) (25). CIITA function is also regulated on MHC genes (3). This raises the possibility that CIITA may through its oligomerization, which has been shown to be medi- also have a more direct function in transcription besides nucleat- ated by amino acids 253–410 (16). Each of the domains and regions ing an enhanceosome. Indeed, as will be discussed below, CIITA listed above are also the targets of multiple post translational mod- functions as a component of the basal transcription machinery. ifications which control their function (14). The expression of the CIITA gene itself is regulated by a complex mechanism involving CIITA FUNCTIONS AS A GENERAL TRANSCRIPTION FACTOR four promoters and five enhancers that combine to form a dynamic AND FUNCTIONAL HOMOLOG OF TAF1 chromatin structure (26, 27). Thus, CIITA is an extremely com- The basal transcriptional machinery requires the assembly on the plex, unstable, and short lived protein, suggesting that its presence core promoter of a pre-initiation complex (PIC) that plays a cen- and function are tightly regulated. tral role in regulating transcription initiation. PIC assembly is initiated by the binding of the TFIID general transcription fac- CIITA FUNCTIONS AS A TRANSACTIVATOR BY NUCLEATING tor complex – composed of the TATA-binding protein (TBP) and AN ENHANCEOSOME a set of TBP-associated factors (TAFs) – to the core promoter (34). The role of CIITA as a central component of an enhanceosome The largest factor in the TFIID complex, TAF1, has AT and kinase has been characterized primarily for the MHC genes. MHC class activities both of which are essential for transcription initiation II genes are transcriptionally controlled via conserved cis-acting (35, 36). In early studies from our lab, it was demonstrated that elements in their promoters. These elements, named the W/S, constitutive transcription of MHC class I genes depends on the AT X, X2, and Y boxes interact with specific trans-activating DNA activity of TAF1: MHC class I expression was abrogated at restric- binding factors to regulate MHC transcription either positively or tive temperatures in TAF1 temperature-sensitive mutants. In con- negatively (28). The DNA binding factors involved, namely RFX trast, CIITA-activated transcription of MHC genes was unaffected (a hetero-multimer consisting of subunits RFX5, RFX-ANK, and under these conditions, and thus independent of TAF1 function RFX-AP), cyclic AMP response element binding protein (CREB), (37). This finding led to our discovery that CIITA, like TAF1, has and NF-Y (A, B, and C), bind directly to the X, X2, and Y boxes an intrinsic AT activity and can bypass the requirement for TAF1 respectively. These factors are constitutively expressed but their (7). Based on these findings, we proposed that CIITA functions as binding
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