Peptides presented on major histocompatibility (MHC) class I molecules form an essential part of the immune system's capacity to detect virus-infected or transformed cells. Earlier works have shown that pioneer translation peptides (PTPs) for the MHC class I pathway are as efficiently produced from introns as from exons, or from mRNAs targeted for the nonsense-mediated decay pathway. The production of PTPs is a target for viral immune evasion but the underlying molecular mechanisms that govern this non-canonical translation are unknown. Here, we have used different approaches to show how events taking place on the nascent transcript control the synthesis of PTPs and full-length proteins. By controlling the subcellular interaction between the G-quadruplex structure (G4) of a gly-ala encoding mRNA and nucleolin (NCL) and by interfering with mRNA maturation using multiple approaches, we demonstrate that antigenic peptides derive from a nuclear non-canonical translation event that is independently regulated from the synthesis of full-length proteins. Moreover, we show that G4 are exploited to control mRNA localization and translation by distinguishable mechanisms that are targets for viral immune evasion.
- MeSH
- antigeny genetika imunologie MeSH
- buněčné jádro genetika imunologie MeSH
- G-kvadruplexy MeSH
- imunitní únik genetika imunologie MeSH
- lidé MeSH
- messenger RNA genetika imunologie MeSH
- MHC antigeny I. třídy genetika imunologie MeSH
- nonsense mediated mRNA decay genetika imunologie MeSH
- peptidy genetika imunologie MeSH
- proteosyntéza genetika imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Mutations in the C1 inhibitor (C1INH) encoding gene, SERPING1, are associated with hereditary angioedema (HAE) which manifests as recurrent submucosal and subcutaneous edema episodes. The major C1INH function is the complement system inhibition, preventing its spontaneous activation. The presented study is focused on SERPING1 exon 3, an alternative and extraordinarily long exon (499 bp). Endogenous expression analysis performed in the HepG2, human liver, and human peripheral blood cells revealed several exon 3 splicing variants alongside exon inclusion: a highly prevalent exon skipping variant and less frequent +38 and -15 variants with alternative 3' splice sites (ss) located 38 and 15 nucleotides downstream and upstream from the authentic 3' ss, respectively. An exon skipping variant introducing a premature stop codon, represented nearly one third of all splicing variants and surprisingly appeared not to be degraded by NMD. The alternative -15 3' ss was used to a small extent, although predicted to be extremely weak. Its use was shown to be independent of its strength and highly sensitive to any changes in the surrounding sequence. -15 3' ss seems to be co-regulated with the authentic 3' ss, whose use is dependent mainly on its strength and less on the presence of intronic regulatory motifs. Subtle SERPING1 exon 3 splicing regulation can contribute to overall C1INH plasma levels and HAE pathogenesis.
- MeSH
- alternativní sestřih genetika MeSH
- buněčné jádro genetika MeSH
- buňky Hep G2 MeSH
- exony genetika MeSH
- inhibiční protein komplementu C1 genetika MeSH
- lidé MeSH
- malá interferující RNA metabolismus MeSH
- místa sestřihu RNA genetika MeSH
- mutace genetika MeSH
- nonsense mediated mRNA decay genetika MeSH
- sekvence nukleotidů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Nonsense mediated RNA decay (NMD) is well-known as an RNA quality control mechanism that sequesters a substantial portion of RNA from expression by targeting it for degradation. However, a number of recent studies across a range of organisms indicate a broader role for NMD in gene regulation and transcriptome homeostasis. Here we propose a novel role for NMD as a buffering system with the capability of accumulating and subsequently releasing a wide spectrum of cryptic genetic variation in response to environmental stimuli, and hence facilitating adaptive evolution. We discuss this role for NMD in the context of evolution of plant pathogen defense, whereby NMD may promote rapid diversification of intracellular immune receptors by mitigating the potentially harmful impact of their newly formed variants on plant fitness.
