Translation-coupled mRNA quality control mechanisms

Abstract

mRNA surveillance pathways are essential for accurate gene expression and to maintain translation homeostasis, ensuring the production of fully functional proteins. Future insights into mRNA quality control pathways will enable us to understand how cellular mRNA levels are controlled, how defective or unwanted mRNAs can be eliminated, and how dysregulation of these can contribute to human disease. Here we review translation-coupled mRNA quality control mechanisms, including the non-stop and no-go mRNA decay pathways, describing their mechanisms, shared trans-acting factors, and differences. We also describe advances in our understanding of the nonsense-mediated mRNA decay (NMD) pathway, highlighting recent mechanistic findings, the discovery of novel factors, as well as the role of NMD in cellular physiology and its impact on human disease.

Keywords: No-go mRNA decay; Non-stop mRNA decay; Nonsense-mediated mRNA decay; RNA quality control; UPF1.

Figure 1. Translation‐coupled mRNA quality control mechanisms

(A) Stability of mRNAs is affected by translation. Several layers of regulation monitor the efficiency of mRNA translation, including the translation rate, amino acid composition, and mRNA secondary structures. (B) The mRNA translation rate is slowed down when the ribosome encounters sub‐optimal codons leading to a decrease in mRNA stability. (C) No‐go mRNA decay (NGD) is triggered by the presence of mRNA secondary structures leading to ribosome stalling. (D) The absence of a stop codon results in slowing of the ribosome reading through the poly (A) tail triggering the non‐stop mRNA decay (NSD) pathway. (E) Recognition of a PTC sets in motion a cascade of event involving the UPF family of proteins, resulting in mRNA degradation by the nonsense‐mediated mRNA decay (NMD) pathway.

Figure 2. Steps and factors involved in no‐go and non‐stop mRNA decay

Flow chart depicting steps and trans‐acting factors shared or unique to these two RNA quality control pathways from initial ribosome collision, ubiquitination and endonucleolytic cleavage to ultimate mRNA degradation and ribosome recycling. S. cerevisiae homologs are indicated in brackets.

Figure 3. UPF1 structure, binding sites, and known mutations

Diagram depicting the domain structure of the canonical UPF1_SL isoform, highlighting key residues for its phosphorylation and ATP binding capacity. An isoform generated via alternative splicing, UPF_LL, includes an extra 11 amino acid extended regulatory region, while all other structural elements remain the same. Mutations and their effect on UPF1 function are indicated by the colored boxes. Some mutations in UPF1 have the capacity to eliminate NMD function, whilst some mutations sustain functional NMD. All residue numbers relate to the canonical UPF1_SL isoform.

Figure 4. Mechanism of NMD activation

Schematic depicting the widely accepted molecular events leading to the assembly of the surveillance complex (SURF), its transition to the decay‐inducing complex (DECID) leading to UPF1 phosphorylation and recruitment of SMG6 and/or SMG5/SMG7 that elicit mRNA degradation.

Figure 5. Localized NMD response at the ER

NBAS localizes to the outside membrane of the endoplasmic reticulum (ER), in the vicinity of the translocon, where it recruits the core NMD factor UPF1 to activate a local NMD response at the ER (Longman et al, 2020).