No-nonsense: insights into the functional interplay of nonsense-mediated mRNA decay factors

Abstract

Nonsense-mediated messenger RNA decay (NMD) represents one of the main surveillance pathways used by eukaryotic cells to control the quality and abundance of mRNAs and to degrade viral RNA. NMD recognises mRNAs with a premature termination codon (PTC) and targets them to decay. Markers for a mRNA with a PTC, and thus NMD, are a long a 3′-untranslated region and the presence of an exon-junction complex (EJC) downstream of the stop codon. Here, we review our structural understanding of mammalian NMD factors and their functional interplay leading to a branched network of different interconnected but specialised mRNA decay pathways. We discuss recent insights into the potential impact of EJC composition on NMD pathway choice. We highlight the coexistence and function of different isoforms of up-frameshift protein 1 (UPF1) with an emphasis of their role at the endoplasmic reticulum and during stress, and the role of the paralogs UPF3B and UPF3A, underscoring that gene regulation by mammalian NMD is tightly controlled and context-dependent being conditional on developmental stage, tissue and cell types.

Nonsense-Mediated mRNA Decay Factor Functions in Human Health and Disease

“…In fact, different NMD pathways were identified, each requiring distinct combinations of NMD factors [ 13 , 14 ]. All NMD pathways have in common that they involve UPF1, which, therefore, is considered as the key NMD factor ( Figure 1 ) (reviewed in [ 14 , 28 , 29 ]).…”

“…UPF1 is highly conserved in eukaryotes. It comprises a central helicase domain, flanked by an upstream cysteine-histidine-rich (CH) domain and a downstream serine-glutamine-rich (SQ) domain ( Figure 2 ) [ 29 , 51 , 52 , 77 , 79 , 80 ]. UPF1’s central role in NMD relies on its capacity to bind RNA, which is supported by its helicase domain.…”

“…The helicase domain structure of UPF1 is well-characterised [ 52 , 80 ]. A wide range of conformations have been observed in structural studies, shedding light on the molecular dynamics linking UPF1’s RNA-associated catalytic functions to ATP-binding and hydrolysis (reviewed in [ 29 ]). ATP binding hinders the binding of RNA by UPF1 [ 81 ], and UPF1’s ATPase activity is essential to NMD [ 38 , 83 , 84 ].…”

“…Several of these phosphorylation sites share a consensus leucine-serine-glutamine (LSQ) sequence [ 99 ]. The structural study of the SMG1–8–9 kinase complex with a peptide mimicking UPF1 residues 1074–1084 (part of the SQ domain) reveals that these LSQ motifs bind within a hydrophobic cage in the vicinity of the SMG1 kinase active site [ 29 , 100 ]. These data highlight the importance of UPF1’s LSQ motifs for optimal phosphorylation specificity and efficiency of the SMG1–8–9 kinase complex.…”

“…UPF1’s CH domain is a good illustration of UPF1’s functions, which remain poorly understood. Structural studies of the CH domain of UPF1 showed a unique association of two RING-box-like modules [ 29 , 52 , 79 ], which are characteristic of some families of E3 ubiquitin ligase enzymes. Interestingly, biochemical studies showed that yeast Upf1 self-ubiquitinates when Upf3 and the E2 ubiquitin-conjugating enzyme Ubc3 are present [ 103 ].…”