Dendritic Cell-specific MHC Class II Transactivator Contains a Caspase Recruitment Domain That Confers Potent Transactivation Activity

Nickerson, Kevin M.; Sisk, Tyler J.; Inohara, Naohiro; Yee, Christina S.K.; Kennell, Jennifer; Cho, Min Chul; Yannie, Paul J.; Núñez, Gabriel; Chang, Cheong Hee

doi:10.1074/jbc.m101295200

Cited by 69 publications

(65 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The N-terminus of DC-CASPIC is identical to the previously reported CARD-like domain of DC-CIITA (Nickerson et al, 2001). To examine whether an intact CARD-like domain is required for its mitochondrial localization, plasmid DNA constructs encoding for three truncated myc-tagged DC-CASPIC proteins (DC-CASPIC(1-34)-Myc, DC-CASPIC (1-69)-Myc and DC-CASPIC(1-95)-Myc), which include amino acid residue 1-34, 1-69 and 1-95, respectively, were generated ( , followed by FITC-and cy3-conjugated secondary antibodies, respectively.…”

Section: Dc-caspic Localizes To Mitochondriasupporting

confidence: 73%

“…The product of PII is absent in mice; PIV is more prominent in thymic epithelial cells (TEC) and nonhematopietic origin cells; PIII is a lymphoid promoter that is active in B cells and plasmacytoid DCs (pDCs); PI-controlled transcript is specifically expressed in DC and the translational product is called CIITA type I or DC-CIITA (Muhlethaler-Mottet et al, 1997). In comparison to the products from PIII and PIV, the CIITA protein synthesized from PI has an extra caspase recruitment domain, caspase recruitment domain (CARD)-like domain (Nickerson et al, 2001). However, DC-CIITA has a higher transactivation activity than type III CIITA, which does not contain a CARD-like domain.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A novel CARD containing splice-isoform of CIITA regulates nitric oxide synthesis in dendritic cells

et al. 2010

View full text Add to dashboard Cite

MHC class II expression is controlled mainly at transcriptional level by class II transactivator (CIITA), which is a non-DNA binding coactivator and serves as a master control factor for MHC class II genes expression. Here, we describe the function of a novel splice-isoform of CIITA, DC-expressed caspase inhibitory isoform of CIITA (or DC-CASPIC), and we show that the expression of DC-CASPIC in DC is upregulated upon lipopolysaccharides (LPS) induction. DC-CASPIC localizes to mitochondria, and protein-protein interaction study demonstrates that DC-CASPIC interacts with caspases and inhibits its activity in DC. Consistently, DC-CASPIC suppresses caspases-induced degradation of nitric oxide synthase-2 (NOS2) and subsequently promotes the synthesis of nitric oxide (NO). NO is an essential regulatory molecule that modulates the capability of DC in stimulating T cell proliferation/activation in vitro; hence, overexpression of DC-CASPIC in DC enhances this stimulation. Collectively, our findings reveal that DC-CASPIC is a key molecule that regulates caspases activity and NO synthesis in DC.

show abstract

Section: Dc-caspic Localizes To Mitochondriasupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

A novel CARD containing splice-isoform of CIITA regulates nitric oxide synthesis in dendritic cells

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Each of the three active CIITA promoters encodes a distinct first exon to the CIITA protein. The use of promoter I (PI) provides CIITA with the greatest transcriptional potential (31). Understanding the regulation of CIITA in different cell types and in response to different mediators will help uncover the signaling pathways involved and also the distinct functions that different CIITA types may play.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Class II MHC Pathway in Primary Human Monocytes by Granulocyte-Macrophage Colony-Stimulating Factor

Hornell

Beresford

Bushey

et al. 2003

The Journal of Immunology

View full text Add to dashboard Cite

GM-CSF stimulates the growth and differentiation of hematopoietic progenitors and also affects mature cell function. These effects have led to the use of GM-CSF as a vaccine adjuvant with promising results; however, the mechanisms underlying GM-CSF-mediated immune potentiation are incompletely understood. In this study, we investigated the hypothesis that the immune stimulatory role of GM-CSF is in part due to effects on class II MHC Ag presentation. We find that, in primary human monocytes treated for 24–48 h, GM-CSF increases surface class II MHC expression and decreases the relative level of the invariant chain-derived peptide, CLIP, bound to surface class II molecules. GM-CSF also increases expression of the costimulatory molecules CD86 and CD40, but not the differentiation marker CD1a or CD16. Furthermore, GM-CSF-treated monocytes are better stimulators in a mixed leukocyte reaction. Additional analyses of the class II pathway revealed that GM-CSF increases total protein and RNA levels of HLA-DR, DM, and DOα. Expression of class II transactivator (CIITA) types I and III, but not IV, transcripts increases in response to GM-CSF. Furthermore, GM-CSF increases the amount of CIITA associated with the DR promoter. Thus, our data argue that the proinflammatory role of GM-CSF is mediated in part through increased expression of key molecules involved in the class II MHC pathway via induction of CIITA.

show abstract

“…Alternative splicing of these transcripts produces isoform-specific mRNAs that differ in the first exon, so that isoforms share four common domains (acidic domain, proline/serine/threonine-rich domain, GTP binding domain, and leucine-rich repeats) but have unique N-terminal sequences (14). DC have been reported to express all three isoforms of CIITA: type I (expressed only in cells of the monocyte lineage and containing a unique N-terminal caspase recruitment domain), type III (also expressed in B cells), and type IV (whose expression is induced by IFN-␥) (13,(15)(16)(17). Type I and type III CIITA comprise most of the CIITA expressed by immature DC, but maturation induces a precipitous decline in levels of type I and type III CIITA mRNA and protein (16,18).…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

“…The following DNA constructs were as described previously: FLAGtagged type I and type III CIITA, and the expression vector pcDNA3 (15); CIITA domain mutants encoding residues 1-331, 408 -857, and 990-1130 (7); the D1 luciferase reporter construct containing the mouse IL-10 promoter (802 bp) in pGL-3 Basic vector (21,22); CMV promoter-driven ␤-galactosidase (␤-gal) (6).…”

Section: Dna and Transfections For Il-10 Reporter Assaysmentioning

confidence: 99%

Enhanced Production of IL-10 by Dendritic Cells Deficient in CIITA

Yee

Yao

et al. 2005

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Dendritic cells (DC) are professional APCs that play a critical role in regulating immunity. In DC, maturation-induced changes in MHC class II expression and Ag presentation require transcriptional regulation by CIITA. To study the role of CIITA in DC, we evaluated key cell functions in DC from CIITA-deficient (CIITA−/−) mice. The ability to take up Ag, measured by fluid phase endocytosis, was comparable between CIITA−/− and control DC. Although CIITA−/− DC lack MHC class II, they maintained normal expression of costimulatory molecules CD80, CD86, and CD40. In contrast, CIITA−/− DC activated with LPS or CpG expressed increased IL-10 levels, but normal levels of TNF-α and IL-12 relative to control. Enhanced IL-10 was due to greater IL-10 mRNA in CIITA−/− DC. Aβ−/− DC, which lack MHC class II but express CIITA normally, had exhibited no difference in IL-10 compared with control. When CIITA was cotransfected with an IL-10 promoter-reporter into a mouse monocyte cell line, RAW 264.7, IL-10 promoter activity was decreased. In addition, reintroducing CIITA into CIITA−/− DC reduced production of IL-10. In all, these data suggest that CIITA negatively regulates expression of IL-10, and that CIITA may direct DC function in ways that extend beyond control of MHC class II.

show abstract

Dendritic Cell-specific MHC Class II Transactivator Contains a Caspase Recruitment Domain That Confers Potent Transactivation Activity

Cited by 69 publications

References 29 publications

A novel CARD containing splice-isoform of CIITA regulates nitric oxide synthesis in dendritic cells

A novel CARD containing splice-isoform of CIITA regulates nitric oxide synthesis in dendritic cells

Regulation of the Class II MHC Pathway in Primary Human Monocytes by Granulocyte-Macrophage Colony-Stimulating Factor

Enhanced Production of IL-10 by Dendritic Cells Deficient in CIITA

Contact Info

Product

Resources

About