RNA binding proteins as regulators of immune cell biology

Abstract

Sequence-specific RNA binding proteins (RBP) are important regulators of the immune response. RBP modulate gene expression by regulating splicing, polyadenylation, localization, translation and decay of target mRNAs. Increasing evidence suggests that RBP play critical roles in the development, activation and function of lymphocyte populations in the immune system. This review will discuss the post-transcriptional regulation of gene expression by RBP during lymphocyte development, with particular focus on the Tristetraprolin family of RBP.

Keywords: cell activation; gene regulation; inflammation.

Figure 1

Competitive binding by human antigen R (HuR) and Tis11 can direct alternative target mRNA fates. HuR and Tis11 can compete for the same binding sequences, resulting in opposing mRNA fates. (a) Competition for binding to target mRNA is determined by the affinity each RNA binding proteins (RBP) has to shared binding sequences. (b) The relative expression of these RBP will affect competitive binding. (c) Post‐translational regulation of RBP, for example via phosphorylation, affects their ability to bind to target mRNAs.

Figure 2

Phosphorylation‐mediated regulation of Tis11 downstream of antigen/cytokine receptor signalling. Tis11 is regulated downstream of antigen/cytokine signalling which culminates in phosphorylation of specific serine residues on the protein. (a) Dephosphorylated Tis11 regulates target mRNA expression negatively through binding specific adenosine–uridine‐rich elements (AREs) in the 3′UTR. (b) Tis11 targets mRNA to sites of degradation such as processing bodies. (c) Tis11 recruits mRNA degradation machinery. (d) Phosphorylation of Tis11 results in 14‐3‐3 binding and regulates its function negatively, allowing Tis11 target mRNAs to be translated and expressed. (e) Phosphorylated Tis11 has reduced binding affinity for target mRNAs. (f) Phosphorylation may result in the exclusion Tis11 from sites of degradation such as procession bodies. (g) Phosphorylated Tis11 is deficient in its ability to recruit mRNA decay machinery. (h) As a result of this there may be increased translation of Tis11b target mRNAs.