Initiation is a critical step in translation, during which the ribosome lands on the start codon and sets the correct reading frame for mRNA decoding. The rate and efficiency of translation are largely determined by initiation, which is therefore the preferred target of translation regulation mechanisms. Initiation has incurred an extensive evolutionary divergence among the primary domains of cell descent. The Archaea, albeit prokaryotes, have an initiation mechanism and apparatus more complex than those of the Bacteria; the molecular details of archaeal initiation are just beginning to be unravelled. The most notable aspects of archaeal initiation are the presence of two, perhaps three, distinct mechanisms for mRNA–ribosome interaction and the presence of a relatively large set of IFs (initiation factors), several of which are shared exclusively with the Eukarya. Among these, the protein termed a/eIF2 (archaeal/eukaryotic IF2) and aIF6 (archaeal IF6) are of special interest, since they appear to play key regulatory roles in the Eukarya. Studies of the function of these factors in Archaea have uncovered new features that will help to elucidate their conserved and domain-specific functions.

Translational initiation: an essential yet divergent step of the gene expression process

Initiation is the opening step of protein synthesis, which largely controls its general rate and efficiency. The participants in the initiation reactions are the two ribosomal subunits, tRNAi (initiator tRNA) and a number of accessory proteins [the IFs (initiation factors)] that modulate the whole process.

Strikingly, the mechanism and apparatus for initiation have diverged to a large extent in the three primary domains of life: Bacteria, Archaea and Eukarya. In the Bacteria, the small ribosomal subunit (30S) binds directly to the mRNA, aided by three IFs. IF2 binds tRNAifmet (initiator formylmethionyl-tRNA) and adjusts it in the P site, while IF1 stimulates IF2 activity and IF3 controls the accuracy of codon–anticodon recognition [1]. In the Eukarya, mRNA–ribosome interaction and the selection of the correct initiation codon take place by a ‘scanning’ mechanism, whereby the 40S subunit binds at the capped 5′-end of the mRNA and moves in a 3′-direction until the initiator AUG codon is found [2]. This process is promoted by over a dozen factors [3]. However, the core components of eukaryotic initiation complexes are the proteins called eIF (eukaryotic IF) 2, eIF1 and eIF1A that interact with the 40S subunit forming a 43S complex. eIF2 binds tRNAiMet (initiator methionyl-tRNA) and delivers it to the ribosome. eIF1 and eIF1A stimulate tRNA binding, promote ribosome scanning and control the accuracy of codon–anticodon recognition. In spite of their similar names, few of the factors mentioned are conserved across domains. The only true homologues are eIF1A and bacterial IF1, whereas eIF2 and IF2 are completely unrelated. A homologue of IF2, termed eIF5B, is found in Eukarya, but it does not bind tRNAi and seems to stimulate subunit joining [4].

The Archaea, despite being prokaryotes phenotypically, have an unexpectedly elaborate initiation process [5]. Archaea have at least five IFs: they include homologues of the eukaryotic factors eIF1, eIF1A, eIF2, eIF5B and eIF6 (Table 1). In the last decade, experimental and in silico studies of translation initiation in Archaea have shed some light on the conserved and domain-specific aspects of this fundamental cellular process. The long-held notion that translation initiation evolved independently in Bacteria and Eukarya has been abandoned. It is now clear that initiation has a core of evolutionarily conserved components common to the three domains of life, while each domain has its specific features. The Archaea are especially interesting in that they seem to have multiple mechanisms for mRNA–ribosome interaction, some of which may be evolutionary ‘relics’ from an ancient past.

Table 1
Translation initiation factors in Archaea
Factor Function in Archaea Bacterial homologue Eukaryotic homologue 
aIF1 mRNA binding; fidelity of start codon choice YciH (only a few phyla) aIF1 
aIF1A Unknown IF1 aIF1A 
aIF2/5B Adjusts tRNAi in P site IF2 eIF5B 
aIF2 Binds tRNAiMet – eIF2 
aIF6 Keeps subunits dissociated – eIF6 
Factor Function in Archaea Bacterial homologue Eukaryotic homologue 
aIF1 mRNA binding; fidelity of start codon choice YciH (only a few phyla) aIF1 
aIF1A Unknown IF1 aIF1A 
aIF2/5B Adjusts tRNAi in P site IF2 eIF5B 
aIF2 Binds tRNAiMet – eIF2 
aIF6 Keeps subunits dissociated – eIF6 

mRNA structure and initiation mechanism in Archaea

mRNA structure has a primary importance for translational initiation. Most mRNAs, eukaryotic and prokaryotic alike, possess a 5′-UTR (untranslated region) preceding the coding sequence (or sequences, in the case of prokaryotic polycistronic mRNAs). The 5′-UTR includes sequence/structure determinants involved in ribosome binding and recognition [TIR (translation initiation region)]. In the case of polycistronic mRNAs, each individual cistron is usually preceded by its own TIR elements, often spanning the coding sequence of the preceding cistron. It has long been known that the TIRs of bacterial mRNAs include specific sequence elements guiding ribosome binding, i.e. the SD (Shine–Dalgarno) motifs that interact directly with complementary motifs (anti-SD motifs) in the 16S rRNA. It is equally established that eukaryotic mRNAs do not have SD motifs, but possess specific post-transcriptional modifications [‘cap’ and poly(A) tails] that promote ribosome recognition and binding through the mediation of several IFs. Archaeal mRNAs are seemingly more diverse. Like the bacterial ones, they are very often polycistronic, but display SD motifs only in a minority of cases. Most archaeal mRNAs either lack SD motifs or lack a 5′-UTR entirely, being leaderless. Leaderless mRNAs are particularly prevalent in Archaea, representing over 50% of all mRNAs in some species [68]. Bacteria and Eukarya, albeit very infrequently, also harbour leaderless mRNAs [911].

Initiation on leaderless mRNAs is remarkably interesting. Indeed, it has been shown that such mRNAs are universally translatable by all types of ribosomes, regardless of their source, thus leading to the proposal that they are the ancestral type of mRNA, in general use before the divergence of the three primary domains [12]. The mechanism of leaderless translation is still unclear. In Archaea, and also in Bacteria, it has been shown that the 30S ribosomal subunits can bind to leaderless mRNAs only provided that they are already loaded with initiator tRNA (tRNAifMet or tRNAiMet) [12,13]. However, in Bacteria and Eukarya, it has also been proposed that ‘leaderless’ initiation cannot be carried out by dissociated small ribosomal subunits, but requires instead preformed 70S or 80S ribosomes [1416].

Another debated problem regards initiation on mRNAs endowed with a 5′-UTR, but lacking clearly recognizable SD motifs. mRNA–ribosome interaction guided by SD motifs has long been considered a main feature of prokaryotic initiation, crucial for ensuring translational efficiency. In support of this, in vitro and in vivo mutagenesis experiments in Bacteria and Archaea have suggested that weakening or disrupting SD motifs has adverse effects ranging from diminished expression to total loss thereof [8,17,18]. However, in Archaea, only a minority of cistrons contain SD motifs. Also in Bacteria, it has been shown recently that at least one-third of ORFs (open reading frames) lack SD motifs [19]. In Bacteria, it is known that ribosome binding of SD-less mRNAs is promoted by ribosomal protein S1 [20]. However, a number of bacterial phyla and all Archaea lack an S1 homologue. Therefore the mode of ribosome interaction of leadered mRNAs lacking SD motifs is essentially not yet understood. The few published works on this subject in Archaea give puzzling information. One study that has examined the question in some depth could find no precise correlation with any feature of the mRNA's SD-less UTR and translational efficiency: neither sequence, nor length, nor structure had any meaningful correlation with expression [21]. Thus the authors proposed the existence of a novel and uncharacterized mechanism for ribosomal recognition of these mRNAs in halophilic archaea [21]. Unravelling the different initiation mechanisms in Archaea will also entail the full understanding the role of the various initiation factors. Five initiation factors have been characterized in Archaea so far, but probably more will be discovered in the near future; already, several ribosome-binding proteins that may have a role in translational initiation have been identified. A particularly interesting challenge will be to reach a full understanding of the function of those factors that the Archaea share specifically with the Eukarya, but which are not found in Bacteria. These are the proteins termed a/eIF2 (archaeal/eukaryotic IF2; eIF2 in Eukarya), aIF6 (archaeal IF6; eIF6 in Eukarya).

a/eIF2: a dual function?

Like its eukaryotic homologue eIF2, the G-protein a/eIF2 is a complex of three different subunits, termed α, β and γ. It is well established that, similar to its eukaryotic counterpart, a/eIF2 interacts specifically with Met-tRNAiMet and contributes to its adjustment in the ribosomal P site. However, it remains unclear why the Archaea, unlike Bacteria, should possess an additional trimeric factor for Met-tRNAiMet binding. The tRNAi-binding factor in Bacteria is IF2, which has homologues (termed IF5B) in both Archaea and Eukarya; IF5B proteins, however, do not bind tRNAi [4,22]. In Eukarya, eIF2 plays a pivotal role in translational regulation, and its three subunits have each its specific function. The γ-subunit contains the G-domain for guanine nucleotide binding and, together with the β-subunit, builds the tRNA-binding domain. The α-subunit has a mainly regulatory role. Phosphorylation of eIF2 α-subunit on Ser51 blocks GTP/GDP exchange and therefore recycling of the factor, efficiently shutting off translation [23].

The archaeal factor's subunits have apparently different properties. The γ-subunit contains the G-domain, but, unlike its eukaryotic counterpart, it has a similar affinity for GDP and GTP and a guanine-nucleotide-recycling factor is not needed [24]. The Met-tRNAiMet-binding domain is provided by the α- and γ-subunits, with a very minor participation, if any, of the β-subunit [25]. Since GDP/GTP exchange is spontaneous, the archaeal a/eIF2 α-subunit cannot have a regulatory role similar to that of its eukaryotic counterpart, and it is still uncertain whether it is post-translationally modified in any way. In vitro phosphorylation of Pyrococcus horikoshii a/eIF2 α-subunit on Ser48 was reported a few years ago [26], but the function of the modification was not defined. Trying to replicate that result, we have observed that the a/eIF2 α-subunit of Sulfolobus solfataricus can indeed be phosphorylated in vitro by an S. solfataricus recombinant kinase partially homologous with eukaryotic PKR (double-stranded-RNA-dependent protein kinase) (A. Naspi and P. Londei, unpublished work). However, the in vitro reaction phosphorylates the protein in at least three sites; moreover, it seems to be poorly specific, since most proteins added to the reaction, including BSA, are phosphorylated. Finally, phosphorylation of the α-subunit does not appear to modify any of the properties of the factor. Phospho-α-subunits are readily incorporated in the trimeric factor, and the latter binds GDP/GTP, Met-tRNAiMet and the ribosomes with the same efficiency as the non-phosphorylated a/eIF2. Also, it must be stressed that a study characterizing the phosphoproteome of a halophilic archaeon did not find a/eIF2 among the phosphoproteins [27]. Altogether, the available evidence rather suggests that a/eIF2 is not phosphorylated in vivo in Archaea.

Why, then, have the Archaea evolved a specific trimeric factor for Met-tRNAiMet binding, later inherited by the Eukarya? We cannot yet answer this question, but, as a previous study suggests, a/eIF2 may have additional and previously unsuspected functions besides met-tRNAi-binding [28]. Indeed, it has been shown that a/eIF2 also binds with high affinity to 5′-ends of RNA molecules. Strikingly, this interaction only takes place when 5′-RNA termini carry three phosphate groups. In contrast, 5′-monophosphate or dephosphorylated RNAs have little or no affinity for the factor [28].

Interestingly, 5′-3P-ends of RNA molecules interact with similar affinity with both trimeric a/eIF2 and its isolated γ-subunit, at least in vitro. In vivo, it has been observed that overexpression of the a/eIF2 γ-subunit protects mRNA from degradation [28]; however, it is unknown whether, under normal physiological conditions, the 5′-3P mRNA ends interact with isolated γ-subunits or with the complete factor. A specific role for the γ-subunit in mRNA protection is suggested by the observation that, under normal growth conditions in S. solfataricus, it is at least 3-fold more abundant than the α- and β-subunits (A. Naspi and P. Londei, unpublished work). It is noteworthy that the γ-subunit has a marked resemblance to EF (elongation factor) 1, with which it shares a similar three-dimensional fold including a G-domain and an at least partial tRNA-binding domain (Figure 1). Indeed, the isolated a/eIF2 γ-subunit has a weak tRNA-binding capacity. EFs are evolutionarily ancient proteins, almost certainly present in the last common ancestor of extant cells. It is therefore likely that the a/eIF2 γ-subunit originated from a gene duplication of EF-1 just after the branching of the archaeal domain, and that it preceded the emergence of the α- and β-subunits. As the affinity of a/eIF2 γ for the 5′-3P extremity of RNA molecules is higher than that for tRNA, it is conceivable that the original function of this protein was in mRNA protection from 5′-end degradation. The tRNAi-binding capacity possibly evolved when the emergence of the α-subunit created a stronger tRNA-binding domain, and increased the affinity of the factor for the ribosome as well. It is remarkable that a/eIF2 has an higher affinity for 5′-3P RNA ends than for tRNAi when off the ribosome; only when the factor sits on the ribosome does the binding capacity for tRNAi become higher than that for mRNAs [28]. Much more experimentation is, however, necessary to elucidate fully the dual role of a/eIF2 in Archaea. Among many unanswered questions, it is unknown whether the a/eIF2–mRNA interaction has also a role in translational initiation. That this may be the case is suggested by the fact that mRNA dephosphorylation greatly depresses the in vitro translational efficiency of several S. solfataricus mRNAs (D. Benelli and P. Londei, unpublished work).

The γ-subunit of the IF2 factors is structurally homologous with bacterial EF-Tu

Figure 1
The γ-subunit of the IF2 factors is structurally homologous with bacterial EF-Tu

The guanine-nucleotide-binding domains are indicated by arrows. A zinc-finger domain (Zn finger) specific to the a/eIF2 γ-subunit, possibly involved in rRNA or mRNA binding, is also indicated. P. abyssi, Pyrococcus abyssi; T. thermophilus, Thermus thermophilus.

Figure 1
The γ-subunit of the IF2 factors is structurally homologous with bacterial EF-Tu

The guanine-nucleotide-binding domains are indicated by arrows. A zinc-finger domain (Zn finger) specific to the a/eIF2 γ-subunit, possibly involved in rRNA or mRNA binding, is also indicated. P. abyssi, Pyrococcus abyssi; T. thermophilus, Thermus thermophilus.

aIF6: initiation factor or recycling factor?

aIF6 is a monomeric protein of approx. 25 kDa, strictly homologous with the eukaryotic factor eIF6 and not present in Bacteria. Its function is still unclear in both Archaea and Eukarya.

In Eukarya, eIF6 is an essential protein. It binds to the large ribosomal subunit and was initially characterized as a ribosome anti-association factor. Accordingly, it was assigned a function in translational initiation, namely to prevent premature association of the ribosomal subunits during the formation of 43S initiation complexes and search for the initiation codon [29]. Later data cast much doubt on this conclusion. In yeast, eIF6 does not seem to have a role in translation at all, but rather appears to participate in ribosome biosynthesis [30]. In higher eukaryotes, however, eIF6 is certainly implicated in translation. Homozygous ablation of eIF6 determines early lethality in mice embryos; heterozygous mice are viable and have a reduced rate of protein synthesis. Remarkably, cell explants of heterozygous mice are resistant to oncogene-induced transformation [31]. In line with this result, overexpression of eIF6 has been observed in various natural tumours [32]. Thus eIF6 is a new and promising player in the link between cancer and translational regulation. However, the specific role of eIF6 in translation is not clearly understood so far.

In Archaea, aIF6 interacts strongly with the 50S ribosomal subunits [33]. In S. solfataricus, under normal physiological conditions, there is almost no free aIF6. Most of the factor is ribosome-associated; approximately one in ten 50S subunits carries bound aIF6. Excess amounts of aIF6 inhibit translation in vitro by preventing the formation of 70S ribosomes, thus demonstrating that the protein has a subunit anti-association activity like its eukaryotic homologue [33]. The molecular determinants for the anti-association activity of aIF6 have been determined in S. solfataricus: the protein binds to the central region of the 50S subunits, contacting the rRNA helix 69 and r-protein L14, thereby hindering the formation of certain crucial ‘bridges’ connecting the two ribosomal subunits [33]. The in vivo function of aIF6, however, remains uncharacterized. It is uncertain in which step of initiation aIF6 intervenes, whether it co-operates with other factors, and, if so, which ones. The mechanism of dissociation of aIF6 from the ribosomes is also unknown.

Recent data in eukaryotes suggest the possibility that IF6 may be involved in ribosome recycling during translational termination. Termination is a complex process, involving a number of steps and several rounds of GTP hydrolysis. In Bacteria, RFs (release factors) 1 and 2 recognize stop codons and promote hydrolysis of peptidyl-tRNA, while RF3 mediates release of RF1 and RF1 and dissociates itself after hydrolysing GTP. The resulting post-termination complexes comprise 70S ribosomes, mRNA and deacylated P-site tRNA. Release of mRNA and tRNA is mandatory for ribosome recycling; it requires the essential protein called RRF (ribosome-recycling factor), which, however, has no known homologues in either Archaea or Eukarya. According to a couple of studies [34,35], ribosome recycling in Eukarya is promoted by a new factor termed ABCE1 (ATP-binding cassette E1). It is an ATP-binding protein strictly conserved in all Eukarya and Archaea, never before associated with translation. Initially, ABCE1 (then called RLI) was identified in humans as an inhibitor of RNase L. Only recently was it discovered that ABCE1 also plays a role in translation; initially, the step suggested was initiation, since ABCE1 interacts with certain IFs and its depletion causes accumulation of 80S monosomes [34]. Subsequent studies clarified further the function of the protein, showing that it promotes dissociation into subunits of 80S ribosomes during termination. Successful ribosome dissociation by ABCE1, however, requires the co-operation of eIF6, which would render subunit splitting essentially irreversible [35].

Studies on the archaeal ABCE1 homologue are just beginning. Recent experiments with the S. solfataricus protein have revealed that, like its eukaryotic homologue, it interacts with the small ribosomal subunits and can promote the dissociation of 70S ribosomes (D. Barthelme, P. Londei and R. Tampè, unpublished work). If and how aIF6 also intervenes in the termination process is still under investigation. On the whole, however, the available data suggest that Archaea and Eukarya may share a common translation termination pathway, substantially different from the bacterial one and engaging protein factors specific to the archaeal/eukaryotic branch of the tree of life.

Molecular Biology of Archaea II: A Biochemical Society Focused Meeting held at Robinson College, Cambridge, U.K., 16–18 August 2010. Organized and Edited by Stephen Bell (Oxford, U.K.) and Finn Werner (University College London, U.K.).

Abbreviations

     
  • ABC

    ATP-binding cassette

  •  
  • EF

    elongation factor

  •  
  • IF

    initiation factor

  •  
  • aIF

    archaeal IF

  •  
  • eIF

    eukaryotic IF

  •  
  • a/eIF

    archaeal/eukaryotic IF

  •  
  • RF

    release factor

  •  
  • SD

    Shine–Dalgarno

  •  
  • TIR

    translation initiation region

  •  
  • tRNAi

    initiator tRNA

  •  
  • tRNAifMet

    initiator formylmethionyl-tRNA

  •  
  • tRNAiMet

    initiator methionyl-tRNA

  •  
  • UTR

    untranslated region

Funding

This work was supported by the Ministero dell'Istruzione, dell'Università e della Ricerca Scientifica Progetti di Ricerca di Interesse Nazionale 2007–2009 project ‘Translation initiation in archaea: function and ribosome interaction of the conserved factors aIF1, aIF1A and aIF2/5B’ and by the Cenci-Bolognetti Foundation 2007–2009 project ‘Translational regulation: from the archaea to the eukarya’

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