Transcriptional coactivator CIITA, a functional homolog of TAF1, has kinase activity

Abstract

The Major Histocompatibility Complex (MHC) Class II Transactivator (CIITA) mediates activated immune responses and its deficiency results in the Type II Bare Lymphocyte Syndrome. CIITA is a transcriptional co-activator that regulates γ-interferon-activated transcription of MHC class I and class II genes. It is also a functional homolog of TAF1, a component of the general transcription factor complex TFIID. TAF1 and CIITA both possess intrinsic acetyltransferase (AT) activity that is required for transcription initiation. In response to induction by γ-Interferon, CIITA and it’s AT activity bypass the requirement for TAF1 AT activity. TAF1 also has kinase activity that is essential for its function. However, no similar activity has been identified for CIITA thus far. Here we report that CIITA, like TAF1, is a serine-threonine kinase. Its substrate specificity parallels, but does not duplicate, that of TAF1 in phosphorylating the TFIID component TAF7, the RAP74 subunit of the general transcription factor TFIIF and histone H2B. Like TAF1, CIITA autophosphorylates, affecting its interaction with TAF7. Additionally, CIITA phosphorylates histone H2B at Ser36, a target of TAF1 that is required for transcription during cell cycle progression and stress response. However, unlike TAF1, CIITA also phosphorylates all the other histones. The identification of this novel kinase activity of CIITA further clarifies its role as a functional homolog of TAF1 which may operate during stress and γ-IFN activated MHC gene transcription.

Major histocompatibility complexes are up‐regulated in glomerular endothelial cells via activation of c‐Jun N‐terminal kinase in 5/6 nephrectomy mice

“…CIITA is essential in regulating MHC proteins for both Class I (Gobin, Peijnenburg, Keijsers, & van den Elsen, 1997;Martin et al, 1997) and Class II (Chang, Guerder, Hong, van Ewijk, & Flavell, 1996;Soe, Devaiah, & Singer, 2013;Steimle, Otten, Zufferey, & Mach, 1993;Steimle, Siegrist, Mottet, Lisowska-Grospierre, & Mach, 1994). Mutation of CIITA down-regulates MHC II protein presence (Steimle et al, 1993;Wong et al, 2014), and overexpressing it restores MHC II expression in Class II-depleted cells (Chang, Fontes, Peterlin, & Flavell, 1994;Steimle et al, 1993;van der Stoep et al, 2002).…”

CIITA and Its Dual Roles in MHC Gene Transcription

“…Early studies established that CIITA is a coactivator that nucleates the formation of an enhanceosome with transcription factors binding to enhancer elements in the upstream regions of the MHC genes (5, 6). In addition, more recent studies from our lab have demonstrated that it also functions as a component of the basal transcriptional machinery (7–9). Here we review the two distinct mechanisms by which CIITA regulates transcription of MHC class I and II genes and speculate on how these activities may be interconnected.…”

Identification of a Nuclear Export Sequence in the MHC CIITA

“…CIITA does not bind to DNA directly but rather induces expression of target genes by interacting with other nuclear transcription factors including members of the RFX, NFY, and CREB families (27)(28)(29) and, more recently, has been shown to be a functional homolog of TAF1, one of the components of the general transcription factor TFIID complex (30,31). Structurally, CIITA is a member of the NLR/Caterpillar family of genes (32) and contains a multitude of regulatory domains, including an N-terminal acidic domain responsible for transactivation; a PST domain rich in proline, serine, and threonine residues that show susceptibility to phosphorylation by several different kinases; a GTP binding domain (GBD) involved in regulating self-association, nuclear localization, and promoter transactivation; and a leucine-rich region (LRR) common to all NLR/Caterpillar proteins that modulates complex formation, nuclear localization, and CIITA-mediated gene activation (28,30,33).…”