Expression of CD83 Is Regulated by HuR via a Novel cis-Active Coding Region RNA Element

Abstract

Dendritic cells (DCs) 3 are the most potent antigen-presenting cells of the immune system and are specialized to sensitize helper and killer T cells during the induction of T cell-mediated immunity (1, 2). In fact, DCs are the only antigen-presenting cells that are able to stimulate naive CD4 ϩ and CD8 ϩ T cells and are therefore referred to as "nature's adjuvant."The CD83 molecule is to date the best known marker for fully mature DCs because CD83 is predominantly expressed on the surface of dendritic lineage cells and cannot be detected on immature DC precursors (3-5). Although its exact function remains to be determined, the fact that CD83 expression is activated during DC maturation, together with co-stimulatory molecules such as CD80 and CD86, suggests a functionally important role for CD83 in DC-mediated T cell immunity (6, 7). This notion is also supported by the fact that inhibition of CD83 expression during DC maturation reduces the T cell stimulatory capacity of these DCs in allo-mixed leukocyte reactions (8). A study using the soluble extracellular domain of CD83 has provided the first direct evidence that this specific surface molecule is indeed functionally important for T cell activation; the soluble CD83 protein completely inhibited DC-mediated T cell stimulation in a concentration-dependent manner in vitro (9). These data were subsequently confirmed in an independent study by using CD83-Ig fusion protein (10). Thus, CD83 appears to play an important functional role in the regulation of DC-mediated T cell-specific immune responses. Therefore, the investigation of the regulation of CD83 expression may provide novel opportunities to modulate DC activity and subsequently DC-mediated immune responses.

Pdcd4 directly binds the coding region of c-myb mRNA and suppresses its translation

“…At first glance, it appears unusual that the coding region of an mRNA is the target of a translational regulatory mechanism; however, genome-wide analyses of interactions of regulatory RNA-binding proteins with mRNAs have revealed surprisingly large numbers of interactions that take place in the coding regions of the cognate mRNAs (Hogan et al, 2008;Hafner et al, 2010). Previous studies have also identified specific regulatory proteins that bind to the coding regions of certain mRNAs, such as the thymidylate synthase and dihydrofolate reductase, both of which bind to the coding regions of their own mRNAs (Ercikan-Abali et al, 1997;Lin et al, 2000;Zhang et al, 2010) and the RNA-binding protein HuR, which interacts with the coding region of CD83 RNA (Prechtel et al, 2006). Target sites for microRNAs are also not restricted to the 3 0 -UTRs but can occur in the coding region of certain mRNAs.…”

Phosphorylation of the HuR ligand APRIL by casein kinase 2 regulates CD83 expression

“…The combined data indicated that a TBB-sensitive CK2 enzyme complex that contains the CK2 a 0 regulates CD83 expression at the post-transcriptional level by activation of APRIL, a cellular shuttle factor that is involved in nucleocytoplasmic transport and, thereby, in cytoplasmic accumulation of CD83 mRNA [32,35]. …”

“…In contrast, it has been recently shown that the nucleocytoplasmic transport of a small subset of cellular messages, including the CD83 mRNA, is mediated in activated T cells by the unrelated CRM1 pathway [31]. The subsequent analysis of the CD83 transcript revealed that this mRNA contains in its coding region, a highly structured cis-active RNA sequence, termed the post-transcriptional regulatory element (PRE), and that this RNA element is directly recognized by the cellular RNA-binding shuttle protein HuR [32]. Interestingly, PRE:HuR interaction does not affect, as it was shown with other HuR targets such as early response gene mRNA [33], the stability of this transcript.…”

“…Interestingly, PRE:HuR interaction does not affect, as it was shown with other HuR targets such as early response gene mRNA [33], the stability of this transcript. Instead, this interaction induces the CRM1-dependent cytoplasmic accumulation of CD83 mRNA [32]. In this respect, it is important to note that the interaction of HuR and CRM1 is indirect [34] and is, particularly in case of CD83 mRNA export, accomplished by the HuR protein ligand APRIL (ANP32B) [35].…”

“…It is fair to assume that, as opposed to a pathway that mediates the nuclear export of bulk poly(A) 1 mRNA, this specific export route is more efficient and can be more tightly regulated. With regard to CD83 activity, this mechanism may expedite gene expression during leukocyte activation and differentiation, and thus accelerates adaptive immune responses.The detailed analysis of CD83 mRNA revealed that the coding region of CD83 mRNA contains a cis-active PRE sequence that constitutes a high-affinity RNA-binding site of the cellular HuR shuttling protein and thereby directs CD83 mRNA toward the specific CRM1 nuclear export pathway [32]. The further dissection of this mechanism subsequently revealed that the HuR protein ligand APRIL (ANP32B) acts as an adaptor that connects the HuR-bound CD83 transcript with the CRM1 export receptor [35].…”