New Functions of the Major Histocompatibility Complex Class II-Specific Transcription Factor RFXANK Revealed by a High-Resolution Mutagenesis Study

Krawczyk, Michał; Masternak, Krzysztof; Zufferey, Madeleine; Barras, Emmanuèle; Reith, Walter

doi:10.1128/mcb.25.19.8607-8618.2005

Cited by 21 publications

(23 citation statements)

References 52 publications

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“…Notably, RFX5 was recovered as the top partner for RFXANK (Table S2) and one of the top ones for ANKRA2 (Table S1). RFXANK forms a trimeric transcription factor complex with RFX5 and RFXAP (Reith and Mach, 2001;Ting and Trowsdale, 2002) and ANKRA2 may play a similar role (Krawczyk et al, 2005;Long and Boss, 2005). In addition, ANKRA2 coprecipitated HDAC5 (Table S1), which is consistent with the published reports that ANKRA2 interacts with this deacetylase (McKinsey et al, 2006;Wang et al, 2005;Xu et al, 2012).…”

Section: Resultssupporting

confidence: 89%

“…This motif is conserved in the Drosophila homolog of RFX5 and RFX7 ( Figures S3A-S3C). The MPxLPxL motif of RFX5 mediates association with RFXANK (Xu et al, 2012), although this may not be the sole surface for RFXANK association (Krawczyk et al, 2005). Interaction of RFX7 with RFXANK or ANKRA2 has not been reported, but the high similarity to RFX5 suggests that RFX7 may utilize its PxLPxL motif to bind ANKRA2 and RFXANK ( Figure S3).…”

Section: Resultsmentioning

confidence: 96%

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Ankyrin Repeats of ANKRA2 Recognize a PxLPxL Motif on the 3M Syndrome Protein CCDC8

Nie

Jin

et al. 2015

Structure

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Peptide motifs are often used for protein-protein interactions. We have recently demonstrated that ankyrin repeats of ANKRA2 and the paralogous bare lymphocyte syndrome transcription factor RFXANK recognize PxLPxL/I motifs shared by megalin, three histone deacetylases, and RFX5. We show here that that CCDC8 is a major partner of ANKRA2 but not RFXANK in cells. The CCDC8 gene is mutated in 3M syndrome, a short-stature disorder with additional facial and skeletal abnormalities. Two other genes mutated in this syndrome encode CUL7 and OBSL1. While CUL7 is a ubiquitin ligase and OBSL1 associates with the cytoskeleton, little is known about CCDC8. Binding and structural analyses reveal that the ankyrin repeats of ANKRA2 recognize a PxLPxL motif at the C-terminal region of CCDC8. The N-terminal part interacts with OBSL1 to form a CUL7 ligase complex. These results link ANKRA2 unexpectedly to 3M syndrome and suggest novel regulatory mechanisms for histone deacetylases and RFX7.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 96%

Ankyrin Repeats of ANKRA2 Recognize a PxLPxL Motif on the 3M Syndrome Protein CCDC8

Nie

Jin

et al. 2015

Structure

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“…Mutations in the RFX-B gene cause immunodeficiency by producing the bare lymphocyte syndrome (Masternak et al, 1998). Krawczyk et al (2005) indicated that increasing the expression of ANKRA2 activates MHC-II expression, demonstrating that both genes (ANKRA2 and RFX-B) have a similar capacity to activate transcription of the MHC-II genes. Further studies need to be conducted to ascertain whether ANKRA2 is associated with the incidence of multiple pathogenic diseases in cattle.…”

Section: Discussionmentioning

confidence: 99%

“…The Ankyrin-repeat protein 2 (ANKRA2) lies between markers BMS1282 and TGLA304 (W. Snelling, US Meat Animal Research Center, Clay Center, NE, personal communication). This gene may play a major role in the regulation of the major histocompatibility complex class II (MHC-II) genes (Krawczyk et al, 2005;McKinsey et al, 2006). The MHC-II is responsible for the immunological response in livestock.…”

Section: Discussionmentioning

confidence: 99%

A putative quantitative trait locus on chromosome 20 associated with bovine pathogenic disease incidence1,2

Casas

Snowder

2008

Journal of Animal Science

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ABSTRACT:The objective of this study was to detect QTL associated with the incidence of multiple pathogenic diseases in offspring from half-sib bovine families. Four F 1 sires were used to produce offspring: Brahman × Hereford (BH; n = 547), Piedmontese × Angus (PA; n = 209), Brahman × Angus (n = 176), and Belgian Blue × MARC III (n = 246). Treatment records for bovine respiratory disease, infectious keratoconjunctivitis (pinkeye), and infectious pododermatitis (footrot) were available for all of the offspring from birth to slaughter. The incidences of these 3 microbial pathogenic diseases were combined into a single binary trait to represent an overall pathogenic disease incidence. Offspring diagnosed and treated for 1 or more of the previously mentioned pathogenic diseases were coded as a 1 for affected. Cattle with no treatment record were coded as 0 for healthy. A putative QTL for pathogenic disease incidence was detected in the family derived from the BH sire at the genome-wise suggestive level. This was supported by evidence, in the same chromosomal region, of a similar QTL in the family derived from the PA sire. The maximum F-statistic (F = 13.52; P = 0.0003) was located at cM 18. The support interval of the QTL spanned from cM 9 to 28. Further studies should explore this QTL by using other bovine populations to further confirm the QTL and refine the QTL support interval. Offspring inheriting the Hereford allele, in the family from the BH sire, and the Angus allele, in the family from the PA sire, were less susceptible to incidence of pathogenic diseases, when compared with those inheriting the Brahman allele and Piedmontese allele, from the BH and PA sires, respectively.

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“…The Raji, HHK, RJ2.2.5, BLS1, SJO, 6.1.6, DA, and ABI cell lines, as well as CIITA-complemented RJ2.2.5 cells, RFXANK-complemented BLS1 cells, RFX5-complemented SJO cells, and RFXAP-complemented 6.1.6 and DA cells, have all been described (37)(38)(39)(40). The BLS3 cell line was established from a skin biopsy of an MHCII-deficient BLS patient.…”

Section: Cells and Culturementioning

confidence: 99%

The Transcription Factor RFX Protects MHC Class II Genes against Epigenetic Silencing by DNA Methylation

Seguín-Estévez

Palma

Krawczyk

et al. 2009

The Journal of Immunology

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Classical and nonclassical MHC class II (MHCII) genes are coregulated by the transcription factor RFX (regulatory factor X) and the transcriptional coactivator CIITA. RFX coordinates the assembly of a multiprotein “enhanceosome” complex on MHCII promoters. This enhanceosome serves as a docking site for the binding of CIITA. Whereas the role of the enhanceosome in recruiting CIITA is well established, little is known about its CIITA-independent functions. A novel role of the enhanceosome was revealed by the analysis of HLA-DOA expression in human MHCII-negative B cell lines lacking RFX or CIITA. HLA-DOA was found to be reactivated by complementation of CIITA-deficient but not RFX-deficient B cells. Silencing of HLA-DOA was associated with DNA methylation at its promoter, and was relieved by the demethylating agent 5-azacytidine. Surprisingly, DNA methylation was also established at the HLA-DRA and HLA-DQB loci in RFX-deficient cells. This was a direct consequence of the absence of RFX, as it could be reversed by restoring RFX function. DNA methylation at the HLA-DOA, HLA-DRA, and HLA-DQB promoters was observed in RFX-deficient B cells and fibroblasts, but not in CIITA-deficient B cells and fibroblasts, or in wild-type fibroblasts, which lack CIITA expression. These results indicate that RFX and/or enhanceosome assembly plays a key CIITA-independent role in protecting MHCII promoters against DNA methylation. This function is likely to be crucial for retaining MHCII genes in an open chromatin configuration permissive for activation in MHCII-negative cells, such as the precursors of APC and nonprofessional APC before induction with IFN-γ.

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New Functions of the Major Histocompatibility Complex Class II-Specific Transcription Factor RFXANK Revealed by a High-Resolution Mutagenesis Study

Cited by 21 publications

References 52 publications

Ankyrin Repeats of ANKRA2 Recognize a PxLPxL Motif on the 3M Syndrome Protein CCDC8

Ankyrin Repeats of ANKRA2 Recognize a PxLPxL Motif on the 3M Syndrome Protein CCDC8

A putative quantitative trait locus on chromosome 20 associated with bovine pathogenic disease incidence1,2

The Transcription Factor RFX Protects MHC Class II Genes against Epigenetic Silencing by DNA Methylation

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