scholarly journals CIITA is a transcriptional coactivator that is recruited to MHC class II promoters by multiple synergistic interactions with an enhanceosome complex

2000 ◽  
Vol 14 (9) ◽  
pp. 1156-1166
Author(s):  
Krzysztof Masternak ◽  
Annick Muhlethaler-Mottet ◽  
Jean Villard ◽  
Madeleine Zufferey ◽  
Viktor Steimle ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Protein Interactions ◽  
Class Ii ◽  
Hereditary Disease ◽  
Transcriptional Coactivator ◽  
Protein Protein Interactions ◽  
Mhc I ◽  
Mhc Ii ◽  
Class Ii Mhc

By virtue of its control over major histocompatibility complex class II (MHC-II) gene expression, CIITA represents a key molecule in the regulation of adaptive immune responses. It was first identified as a factor that is defective in MHC-II deficiency, a hereditary disease characterized by the absence of MHC-II expression. CIITA is a highly regulated transactivator that governs all spatial, temporal, and quantitative aspects of MHC-II expression. It has been proposed to act as a non-DNA-binding transcriptional coactivator, but evidence that it actually functions at the level of MHC-II promoters was lacking. By means of chromatin immunoprecipitation assays, we show here for the first time that CIITA is physically associated with MHC-II, as well asHLA–DM, Ii, MHC-I, and β2mpromoters in vivo. To dissect the mechanism by which CIITA is recruited to the promoter, we have developed a DNA-dependent coimmunoprecipitation assay and a pull-down assay using immobilized promoter templates. We demonstrate that CIITA recruitment depends on multiple, synergistic protein–protein interactions with DNA-bound factors constituting the MHC-II enhanceosome. CIITA therefore represents a paradigm for a novel type of regulatory and gene-specific transcriptional cofactor.

scholarly journals The MHC Class II Transactivator CIITA: Not (Quite) the Odd-One-Out Anymore among NLR Proteins

2021 ◽  
Vol 22 (3) ◽  
pp. 1074
Author(s):  
Jorge Alfonso León Machado ◽  
Viktor Steimle
Keyword(s):  
Gene Expression ◽  
Mhc Class Ii ◽  
Protein Interactions ◽  
Transcriptional Regulator ◽  
Class Ii ◽  
Class Ii Transactivator ◽  
Mhc I ◽  
Mhc Ii ◽  
Mhc Class Ii Transactivator

In this review, we discuss the major histocompatibility complex (MHC) class II transactivator (CIITA), which is the master regulator of MHC class II gene expression. CIITA is the founding member of the mammalian nucleotide-binding and leucine-rich-repeat (NLR) protein family but stood apart for a long time as the only transcriptional regulator. More recently, it was found that its closest homolog, NLRC5 (NLR protein caspase activation and recruitment domain (CARD)-containing 5), is a regulator of MHC-I gene expression. Both act as non-DNA-binding activators through multiple protein–protein interactions with an MHC enhanceosome complex that binds cooperatively to a highly conserved combinatorial cis-acting module. Thus, the regulation of MHC-II expression is regulated largely through the differential expression of CIITA. In addition to the well-defined role of CIITA in MHC-II GENE regulation, we will discuss several other aspects of CIITA functions, such as its role in cancer, its role as a viral restriction element contributing to intrinsic immunity, and lastly, its very recently discovered role as an inhibitor of Ebola and SARS-Cov-2 virus replication. We will briefly touch upon the recently discovered role of NLRP3 as a transcriptional regulator, which suggests that transcriptional regulation is, after all, not such an unusual feature for NLR proteins.

scholarly journals The Transcriptional Coactivator Cbp Interacts with β-Catenin to Activate Gene Expression

2000 ◽  
Vol 149 (2) ◽  
pp. 249-254 ◽  
Author(s):  
Ken-Ichi Takemaru ◽  
Randall T. Moon
Keyword(s):  
Protein Interactions ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Terminal Region ◽  
Creb Binding Protein ◽  
Transcriptional Coactivator ◽  
Protein Protein Interactions ◽  
Yeast Two Hybrid System ◽  
Recruitment System

β-Catenin plays a pivotal role in the transcriptional activation of Wnt-responsive genes by binding to TCF/LEF transcription factors. Although it has been suggested that the COOH-terminal region of β-catenin functions as an activation domain, the mechanisms of activation remain unclear. To screen for potential transcriptional coactivators that bind to the COOH-terminal region of β-catenin, we used a novel yeast two-hybrid system, the Ras recruitment system (RRS) that detects protein–protein interactions at the inner surface of the plasma membrane. Using this system, we isolated the CREB-binding protein (CBP). Armadillo (Arm) repeat 10 to the COOH terminus of β-catenin is involved in binding to CBP, whereas β-catenin interacts directly with the CREB-binding domain of CBP. β-Catenin synergizes with CBP to stimulate the activity of a synthetic reporter in vivo. Conversely, β-catenin–dependent transcriptional activation is repressed by E1A, an antagonist of CBP function, but not by an E1A mutant that does not bind to CBP. The activation of Wnt target genes such as siamois and Xnr3 in Xenopus embryos is also sensitive to E1A. These findings suggest that CBP provides a link between β-catenin and the transcriptional machinery, and possibly mediates the oncogenic function of β-catenin.

scholarly journals CIITA-driven MHC class II expressing tumor cells can efficiently prime naive CD4+ TH cells in vivo and vaccinate the host against parental MHC-II-negative tumor cells

2016 ◽  
Vol 6 (1) ◽  
pp. e1261777 ◽  
Author(s):  
Farah Bou Nasser Eddine ◽  
Greta Forlani ◽  
Letizia Lombardo ◽  
Alessandra Tedeschi ◽  
Giovanna Tosi ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Th Cells ◽  
Mhc Ii ◽  
Negative Tumor

scholarly journals HLA-class II specificity assessed by high-density peptide microarray interactions

2020 ◽  
Author(s):  
Thomas Osterbye ◽  
Morten Nielsen ◽  
Nadine L. Dudek ◽  
Sri H. Ramarathinam ◽  
Anthony W. Purcell ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Cell Epitope ◽  
Class Ii ◽  
High Density ◽  
Class I Mhc ◽  
Mhc I ◽  
Peptide Epitopes ◽  
Mhc Ii ◽  
Prediction Tools ◽  
Binding Data

AbstractThe ability to predict and/or identify MHC binding peptides is an essential component of T cell epitope discovery; something that ultimately should benefit the development of vaccines and immunotherapies. In particular, MHC class I (MHC-I) prediction tools have matured to a point where accurate selection of optimal peptide epitopes is possible for virtually all MHC-I allotypes; in comparison, current MHC class II (MHC-II) predictors are less mature. Since MHC-II restricted CD4+ T cells control and orchestrate most immune responses, this shortcoming severely hampers the development of effective immunotherapies. The ability to generate large panels of peptides and subsequently large bodies of peptide-MHC-II interaction data is key to the solution of this problem; a solution that also will support the improvement of bioinformatics predictors, which critically relies on the availability of large amounts of accurate, diverse and representative data. Here, we have used recombinant HLA-DRB1*01:01 and HLA-DRB1*03:01 molecules to interrogate high-density peptide arrays, in casu containing 70,000 random peptides in triplicates. We demonstrate that the binding data acquired contains systematic and interpretable information reflecting the specificity of the HLA-DR molecules investigated. Collectively, with a cost per peptide reduced to a few cents combined with the flexibility of recombinant HLA technology, this poses an attractive strategy to generate vast bodies of MHC-II binding data at an unprecedented speed and for the benefit of generating peptide-MHC-II binding data as well as improving MHC-II prediction tools.

scholarly journals CD11cloB220+ interferon-producing killer dendritic cells are activated natural killer cells

2007 ◽  
Vol 204 (11) ◽  
pp. 2569-2578 ◽  
Author(s):  
Christian A.J. Vosshenrich ◽  
Sarah Lesjean-Pottier ◽  
Milena Hasan ◽  
Odile Richard-Le Goff ◽  
Erwan Corcuff ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class Ii ◽  
Nk Cell ◽  
Phenotypic Differences ◽  
Mhc Ii ◽  
Class Ii Mhc

Interferon-producing killer dendritic cells (IKDCs) are a recently described subset of CD11cloB220+ cells that share phenotypic and functional properties of DCs and natural killer (NK) cells (Chan, C.W., E. Crafton, H.N. Fan, J. Flook, K. Yoshimura, M. Skarica, D. Brockstedt, T.W. Dubensky, M.F. Stins, L.L. Lanier, et al. 2006. Nat. Med. 12:207–213; Taieb, J., N. Chaput, C. Menard, L. Apetoh, E. Ullrich, M. Bonmort, M. Pequignot, N. Casares, M. Terme, C. Flament, et al. 2006. Nat. Med. 12:214–219). IKDC development appears unusual in that cytokines using the interleukin (IL)-2 receptor β (IL-2Rβ) chain but not those using the common γ chain (γc) are necessary for their generation. By directly comparing Rag2−/−γc−/y, Rag2−/−IL-2Rβ−/−, Rag2−/−IL-15−/−, and Rag2−/−IL-2−/− mice, we demonstrate that IKDC development parallels NK cell development in its strict IL-15 dependence. Moreover, IKDCs uniformly express NK-specific Ncr-1 transcripts (encoding NKp46), whereas NKp46+ cells are absent in Ncr1gfp/+γc−/y mice. Distinguishing features of IKDCs (CD11cloB220+MHC-II+) were carefully examined on developing NK cells in the bone marrow and on peripheral NK cells. As B220 expression was heterogeneous, defining B220lo versus B220hi NK1.1+ NK cells could be considered as arbitrary, and few phenotypic differences were noted between NK1.1+ NK cells bearing different levels of B220. CD11c expression did not correlate with B220 or major histocompatibility complex (MHC) class II (MHC-II) expression, and most MHC-II+ NK1.1+ cells did not express B220 and were thus not IKDCs. Finally, CD11c, MHC-II, and B220 levels were up-regulated on NK1.1+ cells upon activation in vitro or in vivo in a proliferation-dependent fashion. Our data suggest that the majority of CD11cloB220+ “IKDC-like” cells represent activated NK cells.

scholarly journals Ligation of MHC Class II Induces PKC-Dependent Clathrin-Mediated Endocytosis of MHC Class II

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1810
Author(s):  
Kento Masaki ◽  
Yuhji Hiraki ◽  
Hiroka Onishi ◽  
Yuka Satoh ◽  
Paul A. Roche ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Surface Expression ◽  
Class Ii ◽  
Cellular Functions ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Class Ii Mhc ◽  
Antigen Presenting

In addition to antigen presentation to CD4+ T cells, aggregation of cell surface major histocompatibility complex class II (MHC-II) molecules induces signal transduction in antigen presenting cells that regulate cellular functions. We previously reported that crosslinking of MHC-II induced the endocytosis of MHC-II, which was associated with decreased surface expression levels in murine dendritic cells (DCs) and resulted in impaired activation of CD4+ T cells. However, the downstream signal that induces MHC-II endocytosis remains to be elucidated. In this study, we found that the crosslinking of MHC-II induced intracellular Ca2+ mobilization, which was necessary for crosslinking-induced MHC-II endocytosis. We also found that these events were suppressed by inhibitors of Syk and phospholipase C (PLC). Treatments with a phorbol ester promoted MHC-II endocytosis, whereas inhibitors of protein kinase C (PKC) suppressed crosslinking-induced endocytosis of MHC-II. These results suggest that PKC could be involved in this process. Furthermore, crosslinking-induced MHC-II endocytosis was suppressed by inhibitors of clathrin-dependent endocytosis. Our results indicate that the crosslinking of MHC-II could stimulate Ca2+ mobilization and induce the clathrin-dependent endocytosis of MHC-II in murine DCs.

scholarly journals Reorganization of multivesicular bodies regulates MHC class II antigen presentation by dendritic cells

2001 ◽  
Vol 155 (1) ◽  
pp. 53-64 ◽  
Author(s):  
Monique Kleijmeer ◽  
Georg Ramm ◽  
Danita Schuurhuis ◽  
Janice Griffith ◽  
Maria Rescigno ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Plasma Membrane ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Multivesicular Bodies ◽  
Mhc Ii ◽  
Immature Dendritic Cells ◽  
Class Ii Mhc ◽  
Accessory Molecule ◽  
Class Ii Antigen

Immature dendritic cells (DCs) sample their environment for antigens and after stimulation present peptide associated with major histocompatibility complex class II (MHC II) to naive T cells. We have studied the intracellular trafficking of MHC II in cultured DCs. In immature cells, the majority of MHC II was stored intracellularly at the internal vesicles of multivesicular bodies (MVBs). In contrast, DM, an accessory molecule required for peptide loading, was located predominantly at the limiting membrane of MVBs. After stimulation, the internal vesicles carrying MHC II were transferred to the limiting membrane of the MVB, bringing MHC II and DM to the same membrane domain. Concomitantly, the MVBs transformed into long tubular organelles that extended into the periphery of the cells. Vesicles that were formed at the tips of these tubules nonselectively incorporated MHC II and DM and presumably mediated transport to the plasma membrane. We propose that in maturing DCs, the reorganization of MVBs is fundamental for the timing of MHC II antigen loading and transport to the plasma membrane.

scholarly journals Ubiquitination by March-I prevents MHC class II recycling and promotes MHC class II turnover in antigen-presenting cells

2015 ◽  
Vol 112 (33) ◽  
pp. 10449-10454 ◽  
Author(s):  
Kyung-Jin Cho ◽  
Even Walseng ◽  
Satoshi Ishido ◽  
Paul A. Roche
Keyword(s):  
B Cells ◽  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Mhc Ii ◽  
Class Ii Mhc ◽  
Subsequent Degradation ◽  
Antigen Presenting

MHC class II (MHC-II)-dependent antigen presentation by antigen-presenting cells (APCs) is carefully controlled to achieve specificity of immune responses; the regulated assembly and degradation of antigenic peptide–MHC-II complexes (pMHC-II) is one aspect of such control. In this study, we have examined the role of ubiquitination in regulating pMHC-II biosynthesis, endocytosis, recycling, and turnover in APCs. By using APCs obtained from MHC-II ubiquitination mutant mice, we find that whereas ubiquitination does not affect pMHC-II formation in dendritic cells (DCs), it does promote the subsequent degradation of newly synthesized pMHC-II. Acute activation of DCs or B cells terminates expression of the MHC-II E3 ubiquitin ligase March-I and prevents pMHC-II ubiquitination. Most importantly, this change results in very efficient pMHC-II recycling from the surface of DCs and B cells, thereby preventing targeting of internalized pMHC-II to lysosomes for degradation. Biochemical and functional assays confirmed that pMHC-II turnover is suppressed in MHC-II ubiquitin mutant DCs or by acute activation of wild-type DCs. These studies demonstrate that acute APC activation blocks the ubiquitin-dependent turnover of pMHC-II by promoting efficient pMHC-II recycling and preventing lysosomal targeting of internalized pMHC-II, thereby enhancing pMHC-II stability for efficient antigen presentation to CD4 T cells.

Dendritic cells constitutively present self antigens in their immature state in vivo and regulate antigen presentation by controlling the rates of MHC class II synthesis and endocytosis

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2187-2195 ◽  
Author(s):  
Nicholas S. Wilson ◽  
Dima El-Sukkari ◽  
José A. Villadangos
Keyword(s):  
Dendritic Cells ◽  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Lymphoid Organ ◽  
Lymphoid Organs ◽  
Mhc Ii ◽  
Peptide Complexes ◽  
Self Antigens

Abstract Dendritic cells (DCs) change their antigen-presenting properties during maturation. Immature DCs efficiently capture antigens, but are reported to be impaired in their processing and presenting capacity. Upon an encounter with an inflammatory stimulus, DCs undergo a maturation process that leads to efficient presentation of antigens captured at the time of activation, but precludes processing of antigens encountered at later time points. The mechanisms that underlie these developmental changes are controversial. Thus, it is unclear whether immature DCs can present self antigens, and which are the checkpoints that regulate antigen presentation in immature and mature DCs. We have characterized these mechanisms using DCs derived directly from lymphoid organs. Immature lymphoid organ DCs constitutively presented self peptides bound to major histocompatibility complex class II (MHCII) molecules, but these MHCII-peptide complexes were degraded quickly after their transient expression on the cell surface. During maturation, MHC II endocytosis was down-regulated, so that newly generated MHC II–peptide complexes accumulated on the plasma membrane. Simultaneously, MHC II synthesis was down-regulated, thus preventing the turnover of the MHC II–peptide complexes that accumulated early during maturation. Our results demonstrate that immature DCs constitutively present self antigens in the lymphoid organs and characterize the molecular basis of the capacity of DCs to provide “antigenic memory” in vivo.

MHC Sınıf I ve MHC Sınıf II Gen Düzenlenmesi

2020 ◽  
Vol 8 (3) ◽  
pp. 144-156
Author(s):  
Şule KARATAŞ ◽  
Fatma SAVRAN OĞUZ
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Gene Regulation ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Class I ◽  
Mhc Molecules ◽  
Class Ii Mhc ◽  
Regulation Mechanisms

Introduction: Peptides obtained by processing intracellular and extracellular antigens are presented to T cells to stimulate the immune response. This presentation is made by peptide receptors called major histocompatibility complex (MHC) molecules. The regulation mechanisms of MHC molecules, which have similar roles in the immune response, especially at the gene level, have significant differences according to their class. Objective: Class I and class II MHC molecules encoded by MHC genes on the short arm of the sixth chromosome are peptide receptors that stimulate T cell response. These peptides, which will enable the recognition of the antigen from which they originate, are loaded into MHC molecules and presented to T cells. Although the principles of loading and delivering peptides are similar for both molecules, the peptide sources and peptide loading mechanisms are different. In addition, class I molecules are expressed in all nucleated cells while class II molecules are expressed only in Antigen Presentation Cells (APC). These differences; It shows that MHC class I is not expressed by exactly the same transcriptional mechanisms as MHC class II. In our article, we aimed to compare the gene expressions of both classes and reveal their similarities and differences. Discussion and Conclusion: A better understanding of the transcriptional mechanisms of MHC molecules will reveal the role of these molecules in diseases more clearly. In our review, we discussed MHC gene regulation mechanisms with presence of existing informations, which is specific to the MHC class, for contribute to future research. Keywords: MHC class I, MHC class II, MHC gene regulation, promoter, SXY module, transcription

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