From Yeast to Mammals, the Nonsense-Mediated mRNA Decay as a Master Regulator of Long Non-Coding RNAs Functional Trajectory

Abstract

The Nonsense-Mediated mRNA Decay (NMD) has been classically viewed as a translation-dependent RNA surveillance pathway degrading aberrant mRNAs containing premature stop codons. However, it is now clear that mRNA quality control represents only one face of the multiple functions of NMD. Indeed, NMD also regulates the physiological expression of normal mRNAs, and more surprisingly, of long non-coding (lnc)RNAs. Here, we review the different mechanisms of NMD activation in yeast and mammals, and we discuss the molecular bases of the NMD sensitivity of lncRNAs, considering the functional roles of NMD and of translation in the metabolism of these transcripts. In this regard, we describe several examples of functional micropeptides produced from lncRNAs. We propose that translation and NMD provide potent means to regulate the expression of lncRNAs, which might be critical for the cell to respond to environmental changes.

Keywords: Upf1; lncRNA; micropeptide; nonsense-mediated mRNA decay; translation.

Figure 1

Models of NMD activation mechanisms in mammals and yeast. (a) Mammalian EJC-enhanced NMD. When an EJC remains bound to the RNA downstream of a termination codon, translation termination is inefficient as the EJC interferes with the interaction between PABPC1 and the eukaryotic release factors (eRF1/eRF3). Instead, a SURF complex (Smg1–Upf1–eRF1–eRF3) forms at the level of the PTC. Upf2 and Upf3 are then recruited by the downstream EJC and associate with SURF to form the decay-inducing (DECID) complex. Smg1 phosphorylates Upf1 (P), activating it. Phosphorylated Upf1 promotes RNA decay via Smg6-dependent endonucleolytic cleavage and the Smg5–Smg7-dependent triggering of mRNA deadenylation and decapping. ATP hydrolysis by Upf1 allows the dissociation of the termination complex and the release of the transcript, which can be degraded. Upf1 dephosphorylation by protein phosphatase 2A (PP2A) allows it to return to a dephosphorylated state. The coding region and the UTRs of the mRNA are represented as a large blue arrow and thin blue lines, respectively. See the key for the other symbols. (b) “Faux” 3′ UTR model in yeast. A long 3′ UTR results in inefficient translation termination and Upf1 interaction with eRF1/eRF3, promoting the formation of the Upf1-23 complex (Upf1, Upf2, Upf3) at the level of the terminating ribosome. The Upf2-Upf3 heterodimer is then replaced by Nmd4, Ebs1, the decapping enzyme Dcp2 and its co-factors Dcp1 and Edc3 in the Upf1-decapping complex, leading to RNA decapping. ATP hydrolysis by Upf1 promotes the disassembly of the mRNA/ribosome/Upf1-decapping complex, leading to the release of the transcript which can finally be degraded by Xrn1.

Figure 2

Model of translation-dependent displacement of Upf1 from the mRNA coding region. Upf1 binds promiscuously to any accessible RNA (including NMD non-targets), independently of translation. ATP hydrolysis promotes Upf1 dissociation from non-target RNA regions. Upf1 is also displaced from the coding region by the translating ribosome. This model implies that NMD substrate selection occurs after Upf1 associates with the RNA.

Figure 3

Model of yeast cytoplasmic aslncRNA degradation by NMD. Once in the cytoplasm, an aslncRNA (red) would rapidly be bound by ribosomes, unless in a dsRNA structure with its paired-sense mRNA (blue). This dsRNA might also interfere with Upf1 binding to the aslncRNAs and could be removed by the action of RNA helicases. The detection of a long 3′ UTR would trigger NMD by a mechanism similar to the “faux 3′ UTR”. A Upf1-23 complex would form at the level of the termination codon thanks to the interaction between Upf1 and eRF1/eRF3. The subsequent formation of the Upf1-decapping complex would lead to the decapping of the aslncRNA by Dcp2. Upon ATP-dependent disassembly of the complex, the decapped aslncRNA is degraded by Xrn1. The mRNA and the aslncRNA are represented in blue and red, respectively. Large arrows and thin lines represent the coding regions and the UTRs, respectively. The ribosome and NMD/decapping factors are represented as in Figure 1.

Figure 4

Possible roles of translation and NMD in the metabolism of (as)lncRNAs. Schematic representation of the functional importance of NMD and translation in lncRNAs metabolism (see main text for details). The chain of blue balls represents the micropeptide produced upon the translation of the smORF (red arrow) of the (as)lncRNA. The ribosome, the (as)lncRNA and the NMD/decay factors are represented as above.