RNA metabolism and links to inflammatory regulation and disease

Abstract

Inflammation is vital to protect the host against foreign organism invasion and cellular damage. It requires tight and concise gene expression for regulation of pro- and anti-inflammatory gene expression in immune cells. Dysregulated immune responses caused by gene mutations and errors in post-transcriptional regulation can lead to chronic inflammatory diseases and cancer. The mechanisms underlying post-transcriptional gene expression regulation include mRNA splicing, mRNA export, mRNA localisation, mRNA stability, RNA/protein interaction, and post-translational events such as protein stability and modification. The majority of studies to date have focused on transcriptional control pathways. However, post-transcriptional regulation of mRNA in eukaryotes is equally important and related information is lacking. In this review, we will focus on the mechanisms involved in the pre-mRNA splicing events, mRNA surveillance, RNA degradation pathways, disorders or symptoms caused by mutations or errors in post-transcriptional regulation during innate immunity especially toll-like receptor mediated pathways.

Keywords: Alternative splicing; LPS; Nonsense-mediated decay; Post-transcriptional regulation; RNA decay; Toll-like receptors.

Fig. 1

Spliceosome function in RNA splicing. Splicing is carried out by the spliceosome, which contains five small nuclear ribonucleoproteins that are assembled onto the intron. The Early (E) complex contains the U1 snRNP bound to the 5ʹ splice site. Each element of the 3ʹ splice site is bound by a specific protein: the branch point by SF1, the polypyrimidine tract by U2AF 65, and the AG dinucleotide by U2AF 35. The A complex forms when U2 engages the branch point via RNA/RNA base–pairing. This complex is joined by the U4/5/6 Tri-snRNPs to form the B complex. The B complex is then extensively rearranged to form the catalytic C complex. During this rearrangement the interaction of the U1 and U4 snRNPs are lost and the U6 snRNP is brought into contact with the 5ʹ splice site. The C complex catalyses excision of intron as lariat and ligation of the exon sequences

Fig. 2

Patterns of alternative splicing in NMD. A Intron retaining. B 5ʹUTR-containg uORF. C 3ʹUTR-containing intron. D NMD sensitive long 3ʹUTR. E Alternative exon with PTC

Fig. 3

NMD mechanism in eukaryotic cells. A Activation of NMD by EJCs. Premature termination codon (PTC) recognition relies on the protein complex called the exon-junction complex (EJCs) during the initial round of translation. During translation termination, the mRNA surveillance complex-SURF, comprised of SMGs (SMG1/SMG8/SMG9 complex), UPF1 and eRF, detects the downstream EJC and forms a DECID complex, which induces SMG1-mediated UPF1 phosphorylation. The SMG5/SMG7 complex binds to phospho-S1096 of UPF1 to dissociate the ribosome and release factor from UPF1. SMG6 binds to phospho-T28 of UPF1 to induce UPF1 dissociation from the mRNA. B Aberrant 3ʹUTR-EJC-independent NMD. EJCs are not always required for NMD. In the presence of aberrant 3ʹUTR, translation termination is induced by UPF1 dissociation from the mRNA. This allows for assembly of UPF proteins and recruitment of SMGs independently of an EJC. C mRNA decay by NMD. mRNA degradation is initiated by deadenylation and SMG6 mediated endonucleolytic cleavage, cap hydrolysis and finally XRN1 (5ʹ–3ʹ) and exosome (3ʹ–5ʹ) degradation from both ends of the mRNA fragment