Mechanisms and Regulation of Nonsense-Mediated mRNA Decay and Nonsense-Associated Altered Splicing in Lymphocytes

Jean-Marie Lambert,Laurent Delpy,Jérôme Saulière,Mohamad Omar Ashi,Nivine Srour

doi:10.3390/ijms21041335

Abstract

The presence of premature termination codons (PTCs) in transcripts is dangerous for the cell as they encode potentially deleterious truncated proteins that can act with dominant-negative or gain-of-function effects. To avoid the synthesis of these shortened polypeptides, several RNA surveillance systems can be activated to decrease the level of PTC-containing mRNAs. Nonsense-mediated mRNA decay (NMD) ensures an accelerated degradation of mRNAs harboring PTCs by using several key NMD factors such as up-frameshift (UPF) proteins. Another pathway called nonsense-associated altered splicing (NAS) upregulates transcripts that have skipped disturbing PTCs by alternative splicing. Thus, these RNA quality control processes eliminate abnormal PTC-containing mRNAs from the cells by using positive and negative responses. In this review, we describe the general mechanisms of NMD and NAS and their respective involvement in the decay of aberrant immunoglobulin and TCR transcripts in lymphocytes.

Highlights

The presence of premature termination codons (PTCs) in transcripts is dangerous for the cell as they encode potentially deleterious truncated proteins that can act with dominant-negative or gain-of-function effects
MRNA quality control mechanisms are very important processes that diminish the amount of PTC-containing Ig mRNAs
If an exon junction complex (EJC) is located downstream of a PTC, Nonsense-mediated mRNA decay (NMD) is activated by a complex array of interactions between the ribosome, NMD-associated factors, and EJC components

Summary

Fluctuations of NMD Efficiency during B-Cell Development

The error-prone V(D)J recombination process frequently generates PTCs in lymphocytes [5,84]. The signaling cascade induced by LMP2A protein mimics the B-cell receptor (BCR) tonic signal and induces B lymphocytes to differentiate in the absence of a normal BCR Using this model, we found that approximatively 40% to 60% of PTC-containing Igκ mRNAs were downregulated by a CHX sensitive NMD mode (Figure 2). The reinforcement of NMD controls the amount of truncated Ig, which could impede the efficacy of immune responses As another cellular RNA surveillance pathway limiting the amount of PTC-containing mRNAs, NAS can be activated in response to nonsense mutations [99,100,101]. Studies done by Muhlemann’s laboratory did not reveal any correlation between synthesis of the alternatively spliced mRNA and truncation of the coding region [104] These conflicting reports have rendered the effects of NAS on PTC-containing exons controversial. The production of harmful truncated Ig provides evidence for deleterious NAS activation, confirming the assumption that this RNA surveillance process is highly risky and purposeless

NAS of PTC-containing Ig RNAs during PC Differentiation

Findings

Concluding Remarks