Regulation of CD40 and CD40 ligand by the AT-hook transcription factor AKNA

Abstract

Proteins containing AT hooks bind A/T-rich DNA through a nine-amino-acid motif and are thought to co-regulate transcription by modifying the architecture of DNA, thereby enhancing the accessibility of promoters to transcription factors. Here we describe AKNA, a human AT-hook protein that directly binds the A/T-rich regulatory elements of the promoters of CD40 and CD40 ligand (CD40L) and coordinately regulates their expression. Consistent with its function, AKNA is a nuclear protein that contains multiple PEST protein-cleavage motifs, which are common in regulatory proteins with high turnover rates. AKNA is mainly expressed by B and T lymphocytes, natural killer cells and dendritic cells. During B-lymphocyte differentiation, AKNA is mainly expressed by germinal centre B lymphocytes, a stage in which receptor and ligand interactions are crucial for B-lymphocyte maturation. Our findings show that an AT-hook molecule can coordinately regulate the expression of a key receptor and its ligand, and point towards a molecular mechanism that explains homotypic cell interactions.

A T-cell-specific CD154 transcriptional enhancer located just upstream of the promoter

“…We and others have previously described and characterized the CD154 transcriptional promoter. 2,4,13,[18][19][20][21][22][23] In addition, we have identified a 3 0 CD154 transcriptional enhancer 5 located just downstream of the 3 0 UTR mRNA stability element. 24,25 In vitro, both the hCD154 transcriptional promoter and 3 0 enhancer element are relatively weak, despite the abundant and rapid generation of CD154 mRNA following CD4 T-cell activation.…”

AKNA as Genetic Risk Factor for Cervical Intraepithelial Neoplasia and Cervical Cancer

“…AKNA contains an AT-hook motif of nine amino acids, RTRGRPADS (arginine, threonine, arginine, glycine, arginine, proline, alanine, aspartic acid, serine), which satisfies the consensus requirements of an AT hook DNAbinding motif. The AT-hook is a small motif with a typical sequence signature, in which the tripeptide GRP (Gly 58 , Arg 59 and Pro 60 ) is the centre of the DNA-binding domain (Siddiqa et al;. Besides, AKNA contains multiple PEST protein-cleavage motifs, which have been shown to target proteins of rapid turnover (Chevallier, 1993;Siddiqa et al, 2001) and has three domains located in the PEST regions: Leu10-Thr43, H149-Ser171, and P616-T63.…”

“…The AT-hook is a small motif with a typical sequence signature, in which the tripeptide GRP (Gly 58 , Arg 59 and Pro 60 ) is the centre of the DNA-binding domain (Siddiqa et al;. Besides, AKNA contains multiple PEST protein-cleavage motifs, which have been shown to target proteins of rapid turnover (Chevallier, 1993;Siddiqa et al, 2001) and has three domains located in the PEST regions: Leu10-Thr43, H149-Ser171, and P616-T63. These regions are sites of protein degradation so AKNA is considered to have a short half-life (Siddiqa et al, 2001) ( Figure 1B).…”

“…In addition, the AT-hook motif is considered to be the key to upregulation of expression of immune system co-activator molecules, since it has been shown to be directly involved in inducing the expression of molecules belonging to the TNFR family members. AKNA is mainly expressed in secondary lymphoid organs; it is expressed by germinal centre B lymphocytes during B-lymphocyte differentiation and by natural killer (NK) cells and dendritic cells (Siddiqa et al, 2001). AKNA binds the A/T-rich regulatory elements of the CD40 and CD40L promoters (a key receptor-ligand pair that is critical for antigen-dependent B cell development) and induces its expression (Siddiqa et al, 2001).…”

“…AKNA is mainly expressed in secondary lymphoid organs; it is expressed by germinal centre B lymphocytes during B-lymphocyte differentiation and by natural killer (NK) cells and dendritic cells (Siddiqa et al, 2001). AKNA binds the A/T-rich regulatory elements of the CD40 and CD40L promoters (a key receptor-ligand pair that is critical for antigen-dependent B cell development) and induces its expression (Siddiqa et al, 2001). …”