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Mechanism and regulation of translation in C. elegans *

Robert E. Rhoads § , Tzvetanka D. Dinkova , Nadejda L. Korneeva
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, 71130-3932 USA

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Table of Contents

1. Introduction
2. The Translational machinery
2.1. Mechanism of translation in eukaryotes
2.2. Ribosomes, tRNA, and aminoacyl tRNA synthetases
2.3. Translation factors
3. Structural features of mRNA that affect translational efficiency
3.1. 5'-terminal structures
3.2. 3'-terminal structures
4. Regulation of Translation
4.1. Mechanisms involving translation factor modification
4.2. Mechanisms involving mRNA modification
4.3. Known instances of translational regulation that occur but through unknown mechanisms
4.4. Future directions for protein synthesis research in C. elegans
5. Acknowledgements
6. References


C. elegans represents a favorable system to study the extraordinarily complicated process of eukaryotic protein synthesis, which involves over 100 RNAs and over 200 polypeptides just for the core machinery. Initial research in protein synthesis relied on fractionated mammalian and plant systems, but in the mid-1970s, the powerful genetics of Saccharomyces cerevisiae began to yield new insights for translation in all eukaryotes. C. elegans has many features of higher eukaryotes that are not shared by yeast. This allows protein synthesis researchers to combine biochemistry, cell biology, developmental biology, genetics, and genomics to study regulation of gene expression at the translational level. Most components of the core translational machinery have been identified in C. elegans, including rRNAs, 5S RNA, tRNAs, ribosomal proteins, and aminoacyl tRNA synthetases. C. elegans has amino acid sequence homologs for 56 of the known initiation, elongation, and release factor polypeptides, but few of these have been isolated, functionally identified, or studied at the biochemical level. Similarly, C. elegans has homologs for 22 components of the major signal transduction pathways implicated in control of protein synthesis. The translational efficiency of individual mRNAs relies on cis-regulatory elements that include either a 7-methylguanosine- or 2,2,7-trimethylguanosine-containing cap, the 5'-terminal spliced leader, sequence elements in the 3'-untranslated regions, and the 3'-terminal poly(A) tract. Several key developmental pathways in C. elegans are predominantly governed by translational mechanisms. Some evidence has been presented that well described regulatory mechanisms in other organisms, including covalent modification of translation factors, sequestration of translation factors, and mRNA-specific changes in poly(A) length, also occur in C. elegans. The most interesting unexplored questions may involve changes in the translation of individual mRNAs during development, in response to physiological changes, or after genetic manipulations. Given the highly developed state of C. elegans genomics, it can be expected that future application of computational tools, including data visualization, will help detect new instances of translational control.

1. Introduction

Although "gene expression" is often used synonymously with "transcription", the steady-state levels of proteins in eukaryotic cells are also strongly dependent on translational regulatory mechanisms. Two very different types of translational control occur: global and mRNA-specific. Global control generally involves alterations in the levels, intrinsic activities, or availability of translation factors, whereas mRNA-specific control involves proteins or RNAs that interact with a subset of mRNAs. The overall rate of protein synthesis as well as the translational efficiencies of individual mRNAs are regulated in response to nutritional, hormonal, cellular stress, and developmental signals (Sonenberg et al., 2000).

C. elegans represents an especially favorable system to study the extraordinarily complicated process of eukaryotic protein synthesis, which involves over 100 RNAs and over 200 polypeptides just for the core machinery. The first decades of research in eukaryotic protein synthesis relied on fractionated mammalian and plant systems, with little or no input of genetics. This began to change in the 1970's when the powerful genetics of Saccharomyces cerevisiae was brought to bear on central questions in protein synthesis. From this research came important new insights for translation in all eukaryotes, including discovery of the initiation codon scanning mechanism (Sherman and Stewart, 1975), new protein synthesis factors and regulatory kinases (Hinnebusch, 1997), previously unknown interactions among initiation factors (Asano et al., 2000), the core structure of eIF3, the most complex of the initiation factors (Phan et al., 1998), and new regulatory pathways for the control of protein synthesis (Hinnebusch and Fink, 1983). C. elegans, however, has many features of higher eukaryotes that are not shared by yeast, e.g., tissues, organs, muscles, a nervous system, developmental stages, cell lineages, etc., which involve processes regulated at the translational level. Furthermore, signaling pathways leading to protein synthesis are considerably more similar between C. elegans and humans than between yeast and humans. Thus, C. elegans allows protein synthesis researchers to combine biochemistry, cell biology, genetics, and genomics to understand fundamental questions about the regulation of gene expression at the translational level.

2. The Translational machinery

2.1. Mechanism of translation in eukaryotes

From studies in mammals, yeasts, and plants, it is known that the three steps of protein synthesis are catalyzed by three groups of proteins: initiation, elongation, and release factors (Hershey and Merrick, 2000). A different class of initiation factors (eIF1, eIF2, etc.) catalyzes each step of initiation (Figure 1). [A uniform nomenclature system for translation factors is used here (Clark et al., 1996)]. A ternary complex of eIF2•GTP•Met-tRNAi binds to the 40S ribosomal subunit to form the 43S initiation complex. Recruitment of mRNA to the 43S initiation complex to form the 48S initiation complex requires eIF3, the poly(A)-binding protein (PABP), and the eIF4 proteins. eIF3 is a ~800-kDa multimer that is also required for Met-tRNAi binding to the 40S subunit (molecular masses refer to the mammalian factors). PABP is a 70-kDa protein that specifically binds poly(A) and homo-oligomerizes. The eIF4 factors consist of: eIF4A, a 46-kDa RNA helicase; eIF4B, a 70-kDa RNA-binding and RNA-annealing protein; eIF4H, a 25-kDa protein that acts with eIF4B to stimulate eIF4A helicase activity; eIF4E, a 25-kDa cap-binding protein; and eIF4G, a 185-kDa protein that specifically binds to and co-localizes all of the other proteins involved in mRNA recruitment on the 40S subunit.

 WormBook Mechanism and Regulation of Translation in C. elegans figure 1

Figure 1. Complexes formed and factors participating in the initiation of protein synthesis. 

The 48S complex consists of the eIF4 factors plus PABP, eIF1, eIF1A, eIF3, eIF5, and the eIF2•GTP•Met-tRNAi ternary complex bound to the 40S subunit (Figure 2). It scans until the first AUG in good sequence context is encountered. Scanning requires ATP hydrolysis by eIF4A and the presence of eIF1 and eIF1A. Then eIF5 and eIF5B stimulate GTP hydrolysis by eIF2, followed by 60S joining to form the 80S complex. The released eIF2•GDP is recycled to eIF2•GTP by the guanine nucleotide exchange factor eIF2B. The first elongator aminoacyl-tRNA is brought to the ribosomal A-site by eEF1, after which the first peptide bond is formed. This is followed by a cycle of GTP hydrolysis and exchange. Translocation is catalyzed by eEF2 with another cycle of GTP hydrolysis and exchange. When the ribosome reaches a termination codon, the release factor eRF1 catalyzes termination, and then the GTPase eRF3 ejects eRF1 from the ribosome.

WormBook Mechanism and Regulation of Translation in C. elegans figure 2

Figure 2. Model for the 48S initiation complex. The interactions among eIF1, eIF2, eIF3, eIF4A, eIF4E, eIF4G, eIF5, Mnk, PABP, mRNA, and the 40S ribosomal subunit are shown. The thin line represents mRNA, with the wavy line indicating mRNA secondary structure. Meti is the initiator tRNA. The sizes of protein depictions are roughly proportion to their molecular masses.

2.2. Ribosomes, tRNA, and aminoacyl tRNA synthetases

Many components of the translational machinery have been identified in C. elegans, including rRNAs (Albertson, 1984; Ellis et al., 1986; Files and Hirsh, 1981), ribosomal proteins (Jones and Candido, 1993; Zorio et al., 1994; Gonczy et al., 2000), 5S RNA (Nelson and Honda, 1985), tRNA (Schaller et al., 1991; Tranquilla et al., 1982; Khosla and Honda, 1989; Lee et al., 1990), and aminoacyl tRNA synthetases (Amaar and Baillie, 1993; Gabius et al., 1983; Gonczy et al., 2000).

2.3. Translation factors

Of the 56 initiation factor (eIF), elongation factor (eEF), and release factor (eRF) polypeptides that we and others have identified (Table 1), only ~10% have been isolated and characterized. In the following overview, information not explicitly cited is taken from WormBase, release WS138.

Table 1. C. elegans translational initiation, elongation, and termination factors

Predicted translation factor Transcript (splice variants) CGC/ Other names Predicted identity or function Number of amino acids Identity to C. briggsae/H. sapiens homologs (%)
Initiation factors
eIF1 T27F7.3b -/PIG-B Similar to SUI1 109 100/65
eIF1A H06H21.3 Translation initiation factor 1A 216 72/65
eIF2A E04D5.1 (a, b) Contains similarity to translation initiation factor eIF2A 618, 225 96/34
eIF2α Y37E3.10 Translation initiation factor 2, α subunit 342 88/47
eIF2α K04G2.1 Translation initiation factor 2, α subunit 250 82/58
eIF2γ Y39G10AR.8 Translation initiation factor 2, γ subunit 469 97/72
eIF2B C01G10.9 Translation initiation factor related to eIF-2B,α/β/δ subunits 366 84/43
eIF2Bα ZK1098.4 eIF-2B,α subunit/GCN3 305 94/42
eIF2Bβ Y47H9C.7 eIF-2B,β subunit 340 99.7/25
eIF2Bε D2085.3 eIF-2Bε subunit/ GCD6 666 99.8/23
eIF2Bγ C15F1.4 PPP-1 Translation initiation factor 2B, γ subunit/ pyrophosphorylase family 404 79/29
eIF2C-1 T22B3.2 (a, b) Translation initiation factor 2C and related proteins 1032, 1035 99.9/36
eIF2C-2 ZK757.3 (a, b, c) TAG-76 Translation initiation factor 2C and related proteins 1040, 1037, 55 99.9/42
eIF2C-3 R09A1.1 Translation initiation factor 2C 1121 98/27
eIF3a C27D11.1 EGL-45/eif-3.A Homologs to eIF3a 1076 72/37
eIF3a F55H2.6 CLU-1 Involved in mitochondrial morphology/ distribution 1247 80/40
eIF3b Y54E2A.11a EIF-3.B Translation initiation factor 3, subunit b 725 89/34
eIF3c T23D8.4 EIF-3.C Translation initiation factor 3, subunit c 898 89/39
eIF3d R08D7.3 EIF-3.D Translation initiation factor 3, subunit d 570 94/45
eIF3e B0511.10 EIF-3.E Translation initiation factor 3, subunit e 432 74/49
eIF3f D2013.7 EIF-3.F Translation initiation factor 3, subunit f 294 61/35
eIF3g F22B5.2 EIF-3.G Translation initiation factor 3, subunit g 256 90/31
eIF3h C41D11.2 EIF-3.H Translation initiation factor 3, subunit h 365 97/39
eIF3i Y74C10AR.1 EIF-3.I Translation initiation factor 3, subunit i 327 93/43
eIF3j Y40B1B.5 Translation initiation factor eIF3, p35 subunit 212 69/20
eIF3k T16G1.11 EIF-3.K/pqn-69 Eukaryotic initiation factor 3, p25 subunit 240 89/35
eIF3l C17G10.9 (a.1, a.2, b) RNA polymerase I-associated factor - PAF67 535-537 99/41
eIF4A F57B9.6 INF-1 Protein with high similarity to eukaryotic initiation factor 4A 402 97/72 to eIF4A-2, 71 to eIF4A-1
eIF4A F57B9.3 Translation initiation factor 4F, helicase subunit (eIF4A) and related helicases 363 62/52 to eIF4A-1, 51 to eIF4A-2
eIF4A-3 Y65B4A.6 ATP-dependent RNA helicase FAL1, involved in rRNA maturation 399 93/82 to eIF4A-3, 66 to eIF4A-2, 61 to eIF4A-1
eIF4A-3 F33D11.10 ATP-dependent RNA helicase FAL1, involved in rRNA maturation 399 94/81 to eIF4A-3, 66 to eIF4A-2, 62 to eIF4A-1
eIF4A-p56 C07H6.5 CGH-1 Conserved germline helicase 430 97/71 to DDX6 (p56); 40 to eIF4A-1
eIF4A-47 C26D10.2 (a, b) HEL-1 ATP-dependent RNA helicase 425/268 97/78 to nuclear BAT1 (p47)
eIF4A-DDX47 T26G10.1 ATP-dependent RNA helicase 489 -/61 to DDX47
eIF4A-DDX19 T07D4.4 (a, b, c) ATP-dependent RNA helicase 1022, 638, 613 99.8/49 to DDX19
eIF4A-Prp5 F53H1.1 (a, b) RNA helicase 970, 747 99.9/46 to Prp5
eIF4B Y73B6BL.33 f3 Splicing factor hnRNP-F and related RNA-binding proteins 610 62/31
eIF4E-1 F53A2.6 IFE-1 mRNA cap-binding protein 212 95/40
eIF4E-2 R04A9.4 IFE-2 mRNA cap-binding protein 228 98/40
eIF4E-3 B0348.6 (a, b, c) IFE-3 mRNA cap-binding protein 248, 251, 250 99/47
eIF4E-4 C05D9.5 IFE-4 mRNA cap-binding protein 212 95/30 to eIF4E and 48% to 4E-HP
eIF4E-5 Y57A10A.30 (a, b) IFE-5 mRNA cap-binding protein 240,201 80/40
eIF4G M110.4 (a, b) IFG-1 Translation initiation factor 4F, ribosome/ mRNA-bridging subunit 1155, 1156 99/27
eIF4H T12D8.2 mRNA cleavage and polyadenylation factor I complex, subunit RNA15 207 74/33
eIF5 C37C3.2 (a, b, c) Translation initiation factor 5 436, 402, 413 99/48
eIF5A F54C9.1 IFF-2 Translation initiation factor 5 homolog 161 99/61
eIF5A T05G5.10 IFF-1 Translation initiation factor 5 homolog 161 99/57
eIF5B Y54F10BM.2 Translation initiation factor 5B 1173 82/48
Elongation factors
eEF1A F31E3.5 EFT-3 Translation elongation factor 1α 436 99.8/83
eEF1A R03G5.1 (a, b, c, d) EFT-4 Translation elongation factor 1α 463, 77, 267, 429 99.8/84
eEF1B Y41E3.10 Elongation factor 1 β/δ chain 285 50.5/40
eEF1B F54H12.6 Elongation factor 1 β/δ chain 213 99.5/38
eEF2 F25H5.4 EFT-2 Homolog of translation elongation factor 2 852 89/76
eEF2 ZK328.2 EFT-1 Elongation factor 2 974 99/38
Termination factors
eRF1 T05H4.6(a, b) Peptide chain release factor 1 443, 559 99.8/80
eRF3 H19N07.1 Peptide chain release factor 3 532 99.8/63

eIF2 factors. Both eIF2 and eIF2A catalyze the binding of Met-tRNAi to the 40S ribosomal subunit, the former requiring GTP and the latter, an AUG codon (Zoll et al., 2002). eIF2 is composed of three subunits, α, β, and γ. eIF2β has also been reported to bind mRNA and contributes, together with eIF2γ, to GTP and Met-tRNAi binding. Inactivation of either of these genes is lethal. Surprisingly, eIF2α deletion mutants are viable but have defects in growth and larval development. Yeast eIF2A is not an essential protein, but deletion of C. elegans eIF2A is embryonically lethal. eIF2B is a heteropentameric complex that is essential in yeast and mammalian cells. In C. elegans, inactivation of either the β, γ (Kuwabara and Shah, 1994), or ε subunits causes growth defects, larval arrest, or embryonic lethality.

eIF4 factors. Two splice-variants of eIF4G, encoded by ifg-1, have been identified in C. elegans (Long et al., 2002; Kamath et al., 2003). Although IFG-1 shows low identity to human eIF4G, its role as a translation factor was confirmed by its retention on m7GTP-Sepharose (Keiper and Rhoads, unpublished data) and by its presence in 48S initiation complexes (Dinkova et al., 2005). ifg-1 inactivation results in developmental arrest and embryonic lethality (Long et al., 2002).

eIF4E is encoded by five genes in C. elegans, ife-1 through ife-5 (Jankowska-Anyszka et al., 1998; Keiper et al., 2000; Figure 3). The five proteins can be grouped into three classes based on amino acid sequence identity, cap-binding specificity, and knockout phenotype (Table 2). Some isoforms bind both 2,2,7-trimethylguanosine (TMG)-containing caps as well as 7-methylguanosine (MMG)-containing caps, whereas other isoforms bind only the latter. Cap selectivity is determined by the dimensions and flexibility of the cap-binding pocket (Miyoshi et al., 2002). IFE-1 is bound to P granules through an interaction with PGL-1 and is required for spermatogenesis (Amiri et al., 2001). In the case of IFE-4, inactivation of the gene produces an Egl phenotype, low brood size, and a defect in food sensation (Dinkova et al., 2005). The translational efficiency (polysomal distribution) of only ~1% of mRNAs is affected by ife-4 deletion, but diminished levels of the encoded proteins are consistent with the complex phenotype.

Table 2. Properties of five C. elegans isoforms of eIF4E

Class eIF4E isoform Cap-binding specificity RNAi phenotype Tissue distribution Knockout mutant phenotype Postulated physiological role
A IFE-3 MMG Lethal Soma Germ line Emb General translation
Germ line Spe Regulation of P granules mRNA translation
Viable[a] Soma Unknown Unknown
Viable[a] Unknown Unknown Unknown
Egl Specific mRNA translation during development
References   Jankowska- Anyszka et al., 1998; Keiper et al., 2000; Miyoshi et al., 2002; Stachelska et al., 2002 Keiper et al., 2000; Amiri et al., 2001; Dinkova et al., 2005 Amiri et al., 2001; Dinkova et al., 2005 Amiri et al., 2001; Dinkova et al., 2005 Amiri et al., 2001; Dinkova et al., 2005; Trutschl et al., 2005

aThe combination of RNAi for all three IFEs from Class B is lethal.

WormBook Mechanism and Regulation of Translation inC. elegans figure 3

Figure 3. Homologies among eIF4E isoforms. Amino acid sequence alignments were performed using Vector NTI 9.0.0 with a gap penalty of 3.0 and a gap extension penalty of 0.1. Multiple sequence alignments were used to calculate protein distance values and construct a phylogenetic tree with PHYLIP software on the Institut Pasteur server. eIF4E isoforms from C. elegans are indicated in boxes. NCBI accession numbers are indicated. A. thaliana: At-1, Y10548; At-2, Y10547; At-3, AF028809. C. elegans: Ce-1, NM_067350; Ce-2, NM_075693; Ce-3, NM_171920; Ce-4, AF214651; Ce-5, NM_064207. D. rerio: Dr-1, AF257519; Dr-2, AF176317. D. melanogaster: Dm-1, NM_168334; Dm-2, NM_139795; Dm-3, NM_139903; Dm-4, NM_166870; Dm-5, NM_143397; Dm-6, NM_139937. H. sapiens: Hs-1, M15353; Hs-2, AF047695. M. musculus: Mm-1, M61731; Mm-2, AF068116; Mm-3, AK005054 O.cuniculus: Oc-1, X61939. S. cerevisiae: Sc-1, M15436. S. pombe: Sp-1, X99444; Sp-2, AL031852, T. aestivum: Ta-1, Z12616; Ta-2, M95819.

Nine C. elegans gene products are homologous to eIF4A (Table 1; Roussell and Bennett, 1992; Gonczy et al., 2000). The products of F57B9.6 and F57B9.3 are the most homologous to mammalian eIF4A-1 and eIF4A-2. Others (Y65B4A.6 and F33D11.10) may be involved in splicing or nonsense-mediated decay, similar to mammalian eIF4A-3. Some may play a specific role in germline cells (C07H6.5) or in nuclear export (C26D10.2, T26G10.1, T07D4.4, and F53H1.1). Knockout of any eIF4A-like gene except T07D4.4 causes reproductive defects or embryonic lethality.

Other initiation factors and interacting proteins. eIF1, eIF3, and eIF5 form a multifactor complex in yeast that is required for assembly of the 43S initiation complex. C. elegans eIF5 and eIF1 are essential for growth and embryonic development. There are C. elegans homologs for all 12 eIF3 subunits present in higher eukaryotes (Asano et al., 1997), whereas yeast eIF3 has only five subunits. Loss of eIF3a (C27D11.1) produces an Egl phenotype (Desai and Horvitz, 1989). Both eIF3a and eIF3d are involved in meiotic divisions (Gonczy et al., 2000). Another eIF3a homolog (F55H2.6) is possibly involved in mitochondrial morphology and distribution. Inactivation of eIF5B results in larval arrest and sterility (Maeda et al., 2001). C. elegans contains three PABP homologs. PAB-2 (F18H3.3) has the highest similarity to human cytoplasmic PABP. PAB-1 (Y106G6H.2) is essential for gonad development, and PAB-2 is apparently important for somatic development (Ciosk et al., 2004). PAB-3 (C17E4.5) is more similar to human nuclear PABP and is probably not involved in translation.

Elongation and termination factors C. elegans has two identical eEF1A homologs that are products of different genes, eft-3 (Seydoux and Fire, 1994) and eft-4 (Kamath et al., 2003). EFT-3 is required for embryonic viability, fertility, and germline maintenance. There are two homologs of eEF1B, one of which (F54H12.6) is essential for viability while the other (Y41E3.10) is not. The two eEF2 homologs, EFT-1 (Ofulue and Candido, 1992) and EFT-2 (Ofulue and Candido, 1991; Nollen et al., 2004), are expressed during all stages and are encoded by essential genes. eRF1 has two splice variants whereas eRF3 has only one. Both genes are essential for embryonic and larval development, growth, and locomotion.

3. Structural features of mRNA that affect translational efficiency

A distinctive feature of C. elegans is the presence of polycistronic pre-mRNA transcribed from operons (Blumenthal and Gleason, 2003). Translational control of individual mRNAs relies on cis-regulatory elements that include the cap, the 5'-terminal spliced leader (SL), and additional sequence elements in 5'- and 3'-untranslated regions (UTRs).

3.1. 5'-terminal structures

Spliced leaders. A SL is added to mature mRNA via trans-splicing in nematodes and some other metazoans (Bektesh et al., 1988; Evans et al., 1994; Stover and Steele, 2001). The SL consists of a conserved 22-nt sequence (Conrad et al., 1991; Blumenthal and Steward, 1997). In C. elegans, either SL1 or SL2 (or a variant such as SL3, SL4, etc.) is added to 70% of pre-mRNAs (Blumenthal and Gleason, 2003). SL1 is usually trans-spliced to mRNAs transcribed from the first cistron in an operon or to monocistronic mRNAs, whereas SL2 and its variants are trans-spliced to products of downstream cistrons.

Caps. Those mRNAs that undergo trans-splicing carry a TMG-cap and SL, whereas those that undergo only. cis-splicing carry an MMG-cap and no SL (Van Doren and Hirsh, 1990). The small nuclear RNA that donates the SL contains a TMG-cap (Zorio et al., 1994; Evans et al., 1997). MMG- and TMG-caps are recognized by some but not all eIF4E isoforms (Table 2).

5'UTR. Regulatory features of the 5'UTRs of mRNAs in general involve length, secondary structure, upstream open-reading frames, and specific sequences that interact with RNA binding proteins (Gingras et al., 1999). The trans-splicing processing of many C. elegans mRNAs results in a relatively short 5'UTR in which the SL is located near the AUG codon (Blumenthal and Steward, 1997). A few C. elegans mRNAs, e.g., gna-2, contain long 5'UTRs that harbor upstream open-reading frames (Lee and Schedl, 2004), which have a profound effect on translation efficiency in other organisims (Morris and Geballe, 2000).

Effects of 5'-terminal structures on translational efficiency. Mechanisms of regulation mediated by 5'-terminal structures remain largely unknown for C. elegans. Both MMG- and TMG-containing mRNAs are found on polysomes (Liou and Blumenthal, 1990). In Ascaris lumbricoides, mutations in the SL1 sequence alter efficiency of translation (Maroney et al., 1995). TMG-capped mRNAs are poorly translated in mammalian cell-free translational systems (Darzynkiewicz et al., 1988), but a TMG-cap and SL stimulate translation in an Ascaris suum translation system (Lall et al., 2004). Interestingly, an optimal distance from SL to AUG for translational efficiency can be demonstrated in this system. The translational synergism between cap and poly(A) is greater for TMG than MMG. The well described translational regulator GLD-1 also interacts with 5'UTR sequences (Lee and Schedl, 2004).

3.2. 3'-terminal structures

3'UTR. Translational regulatory elements at the 3'UTR play important roles in C. elegans mRNA expression (see WormBook chapters on Translational control of maternal RNAs and RNA-binding proteins). The elements first described as DREs (direct repeat elements; Goodwin et al., 1993) and later re-named TGEs (tra GLI elements; Jan et al., 1997) are found within the 3'UTR of tra-2 mRNA and negatively regulate its expression in germ line and somatic cells. The trans-acting factor for TGEs was identified as GLD-1 (Jan et al., 1999). A 5-nucleotide sequence element in the 3'UTR of fem-3 mRNA, cuUCUUGu, also exerts translational regulation (Anderson and Kimble, 1997). Another kind of 3'UTR element that represses translation is the lin-4 complementary element (LCE) found in lin-14 and lin-28 mRNAs (Wightman et al., 1993; Seggerson et al., 2002). This element is bound by the microRNA lin-4 (Moss et al., 1997; see C. elegans microRNAs). Mutations in these 3'UTR elements disrupt the translational regulation of their mRNAs (see WormBook chapters referenced above).

poly(A) The poly(A) tract is added by a poly(A) polymerase after specific cleavage during mRNA splicing. The nuclear polyadenylation signal consists of an AAUAAA sequence 20-30 nt upstream of the cleavage site (Blumenthal, 1995; Hajarnavis et al., 2004). In C. elegans, GLD-2 is a putative catalytic subunit of cytoplasmic poly(A) polymerase that is likely recruited to mRNAs by interaction with RNA binding proteins such as GLD-3 (Wang et al., 2002). Cytoplasmic polyadenylation also requires a cytoplasmic polyadenylation element (CPE), located upstream of the polyadenylation site, which is recognized by specific proteins (CPEBs).

Effects of 3'-terminal structures on tranlational efficiency. Although there are many instances in which specific structures in the 3'UTR have been shown to affect translational efficiency in C. elegans and other organisms (Kuersten and Goodwin, 2003), the molecular interactions responsible for these effects are only partially understood. In Xenopus oocytes, CPEB binds and sequesters eIF4E through an intermediary protein, Maskin (Mendez and Richter, 2001). In Drosophila embryos, there is a similar interaction between the 3'UTR-binding factor Smaug and eIF4E, mediated by another protein, Cup (Nelson et al., 2004). However, in C. elegans the translational component(s) involved in GLD-1-mediated regulation remain unknown (Jan et al., 1999; Marin and Evans, 2003; Lee and Schedl, 2004). The other 3'-terminal element, the poly(A) tract, increases the rate of translational initiation in yeast and plants due to the binding of PABP to a specific site near the N-terminus of eIF4G (Tarun and Sachs, 1996; Le et al., 1997; see Figure 2). Poly(A) stabilizes the PABP•eIF4G•eIF4E complex, which in turn leads to enhanced translational re-initiation (Wakiyama et al., 2000). As discussed below, there are several regulatory mechanisms in C. elegans that involve changing the poly(A) length.

4. Regulation of Translation

Many of the translational mechanisms that have been well described and characterized in other organisms (Sonenberg et al., 2000) have not yet been demonstrated in C. elegans. These can be divided into two broad classes, modification of translation factors and modification of mRNA structure. However, the existence of homologous translation factors (Table 1) and signal transduction components (Table 3) suggests that previously discovered mechanisms operate in C. elegans as well.

Table 3. Components of signal transduction pathways implicated in translational control

Predicted signal transduction component Transcript (splice variants) CGC/ Other names Predicted identity or function (WormBase, release WS138)
P70S6K Y47D3A.4 CKU-70 DNA-binding subunit of a DNA-dependent protein kinase
TAP42 Y71H2B.3   Protein phosphatase 2A-associated protein
TIP41 ZK688.9   Uncharacterized conserved protein
SIT4.1 Y75B8A.30 PPH-4.1 Serine/threonine-specific protein phosphatase involved in glycogen accumulation
SIT4.2 Y49E10.3a PPH-4.2 Serine/threonine-specific protein phosphatase involved in glycogen accumulation
Akt C12D8.10 (a, b, c) AKT-1 Ortholog of serine/threonine kinase Akt/PKB
PERK F46C3.1 PEK-1 Human PERK kinase homolog
PEK Y38E10A.8   eIF2α kinase PEK/EIF2AK3
MKK7/JNKK2 F35C8.3 JKK-1 JNK Kinase
MKK4 F42G10.2 MKK-4 MKK (MAP kinase kinase) homolog
MAPK7 C04G6.1 MAP-2 Mitogen-activated protein kinase 7, isoform 1
MAPK7 F09C12.2   Mitogen-activated protein kinase
MAP2K Y54E10BL.6 MEK-2/ LET-537/ GLV-1 MAP kinase kinase or ERK kinase
ERN1/IRE1 C41C4.4 IRE-1 IRE1 kinase related
TOR B0261.2 LET-363 Ortholog of S. cerevisiae Tor1p and Tor2p and human FRAP1
PI3K C46B6.6 SMG-1/ MAB-1 PI-3-kinase-related kinase SMG-1 isoform 2
PI3K like T06E4.3 ATL-1 ATM (ataxia telangectasia mutated)-like
PI4K ZC8.6   Phosphatidylinositol 4-kinase
PI4K C56A3.8   Phosphatidylinositol 4-kinase
Raptor C10C5.6 (a, b) DAF-15 Abnormal dauer formation

4.1. Mechanisms involving translation factor modification

Covalent modification of a translation factor. The unfolded protein response (UPR) is a transcriptional and translational signaling pathway activated by the accumulation of unfolded proteins in the endoplasmic reticulum (ER; Zhang and Kaufman, 2004). This involves activation of an eIF2α kinase, PEK, causing global inhibition of translation initiation and allowing time to remedy the folding problem. C. elegans PEK-1 was expressed in yeast and found to inhibit growth by hyperphosphorylation of eIF2α and inhibition of eIF2B (Sood et al., 2000). UPR gene transcription and survival upon ER stress also requires ire-1-mediated splicing of xbp-1 mRNA (Shen et al., 2001). ire-1/xbp-1 acts with pek-1 in complementary pathways that are essential for worm development, survival, and ER homeostasis. Furthermore, pek-1 mutants have shortened life spans (Harding et al., 2003).

Sequestration of a translation factor. TOR is a highly conserved protein kinase that controls cell growth and division in eukaryotes. In mammals, mTOR regulates translation by phosphorylation of p70 S6 kinase (S6K) and the eIF4E-binding protein 4E-BP1 (Gingras et al., 2001). The latter event releases eIF4E from a sequestered form, making it available to bind eIF4G (Figure 2). Raptor is a mTOR-binding protein that is necessary for the mTOR-catalyzed phosphorylation of 4E-BP1 and S6K (Hara et al., 2002). In yeast, TOR also regulates translation through eIF4E by a mechanism involving the phosphatases Sit4 and PP2A and the phosphatase-binding protein Tap42 (Jiang and Broach, 1999). Tip41 negatively regulates TOR by binding and inhibiting Tap42 (Jacinto et al., 2001).

In C. elegans, cTOR (let-363) deficiency causes developmental arrest and intestinal atrophy (Long et al., 2002). The phenotype resembles that of RNAi knockdown of eIF4G, eIF2α, and eIF2β, but not S6K, Tip41, or Tap42. RNAi of Raptor (daf-15) yields an array of phenotypes resembling those of cTOR knockout. Deficiency of both let-363 (Vellai et al., 2003) and daf-15 (Jia et al., 2004) extends adult lifespan, while mutations in either gene result in dauer-like larval arrest (Jia et al., 2004). To date, a C. elegans 4E-BP1 homolog has not been identified. The protein phas-1 (WP:CE30964; Agostoni et al., 2002; another name for 4E-BP1 is PHAS-I) is unrelated to mammalian and Drosophila 4E-BP1.

The presence of IFE-1 in P granules (Amiri et al., 2001) and its absence from initiation complexes (Dinkova et al., 2005) may represent another regulatory mechanism involving sequestration of a translation factor. A number of mRNAs have been found in P granules, some of which have been shown to be translationally controlled (Schisa et al., 2001). P granules also contain four GLH RNA helicases similar to eIF4A (Gruidl et al., 1996; Kuznicki et al., 2000). In Drosophila, VASA is a germline-specific ATP-dependent RNA helicase, homologous to the GLH proteins, that is required for translation of at least two mRNAs, gurken and nanos, through interaction with eIF5B (Styhler et al., 1998; Johnstone and Lasko, 2004). Also, eIF5A is required for PGL-1 localization (Hanazawa et al., 2004). The presence of all these translational components in P granules may signify regulation of germline-specific mRNA translation.

4.2. Mechanisms involving mRNA modification

The translation of some C. elegans mRNAs is regulated by 3'UTR-binding proteins that alter poly(A) length (Kuersten and Goodwin, 2003). There are four CPEB homologs, CBP-1, CPB-2, CPB-3, and FOG-1 (Luitjens et al., 2000). CPB-1 is essential for progression through meiosis and is present in germ cells just before spermatogenesis. CPB-1 physically interacts with FBF, another RNA-binding protein and 3' UTR regulator. Similarities between FOG-1 and the CPEB proteins of Xenopus and Drosophila suggest that FOG-1 controls germ cell fates by regulating the translation of specific messenger RNAs.

A specific mRNA that undergoes regulated changes in poly(A) length is tra-2 mRNA, whose translation must be repressed for male development. A possible mechanism of action is suggested by the observation that TGEs control the length of the poly(A) tract in a Xenopus system (Thompson et al., 2000). Similarly, a 5-nt element in the 3'UTR of fem-3 mRNA controls the length of the poly(A) tract (Ahringer and Kimble, 1991). fem-3 must be downregulated to allow the switch from spermatogenesis to oogenesis. FBF and Nanos-3 interact with each other and repress translation of fem-3 mRNA (Kraemer et al., 1999). GLD-3 also physically interacts with FBF to interfere with FBF binding to the 3'UTR of fem-3 mRNA (Eckmann et al., 2002). GLD-3 promotes the transition from mitosis to meiosis together with the putative GLD-2 poly(A) polymerase. FBF also binds specifically to elements in the 3'UTR of gld-3S mRNA and regulates gld-3 expression (Eckmann et al., 2004).

4.3. Known instances of translational regulation that occur but through unknown mechanisms

The translation of several other mRNAs is known to be regulated through the 3'UTR, but this cannot yet be explained within the framework of known translational control mechanisms. A 34-nucleotide region of the 3'UTR of glp-1 mRNA contains two regulatory elements, one that represses translation in germ cells and posterior cells of the early embryo, and one that inhibits repressor activity to promote translation in the embryo (Marin and Evans, 2003). GLD-1 binds to this repressor element. MEX-3 is also expressed in anterior blastomere cells and is required for repression of pal-1 mRNA translation (Hunter and Kenyon, 1996; Draper et al., 1996).

A different type of 3'UTR regulation is seen with the heterochronic genes, which are temporally controlled to specify the timing of developmental events. lin-14 and lin-28 encode proteins that are required for temporal execution of cell lineages during larval development. lin-14, lin-28, lin-42, and daf-12 mRNAs contain a conserved element in the 3'UTR, the loss of which causes a gain of function (Seggerson et al., 2002). let-7 encodes a temporally regulated 21-nucleotide RNA that is complementary to elements in heterochonic mRNA 3'UTRs and regulates their translation (Reinhart et al., 2000). A second regulatory RNA, lin-4, negatively regulates lin-14 and lin-28 through RNA-RNA interactions with their 3'UTR (Moss et al., 1997). lin-28 is repressed during normal development by a mechanism that acts on its mRNA after translation initiation (Seggerson et al., 2002).

4.4. Future directions for protein synthesis research in C. elegans

As illustrated throughout this chapter, several key developmental pathways in C. elegans are predominantly governed by translational mechanism. However, translation per se has received little attention. Even though one can find C. elegans homologs for most of the RNAs and proteins that make up the translational machinery (Table 1), few of these have been isolated, functionally identified, or studied at the biochemical level. This deficiency obscures the molecular mechanisms responsible for well characterized physiological processes. Another shortcoming is the absence of a cell-free translation system, although such systems have been developed in two other nematodes, Ascaris lumbricoides (Maroney et al., 1995) and Ascaris suum (Lall et al., 2004). The most interesting unexplored questions may involve changes in the translation of individual mRNAs in various physiological conditions or after genetic manipulations. Given the highly developed state of C. elegans genomics, it can be expected that future application of computational tools, including data visualization (Trutschl et al., 2005), will help detect new instances of translational control.

5. Acknowledgements

This work was supported by Grant GM20818 from the National Institutes of Health. We thank Brett Keiper for sharing preliminary data and for helpful discussions, Aaron Lefebvre for protein sequence alignments and construction of Figure 3, and Lisa Whittington for editorial assistance.

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*Edited by Thomas Blumenthal. Last revised January 12, 2005. Published January 28, 2006. This chapter should be cited as: Rhoads, R. E. et al. Mechanism and regulation of translation in C. elegans (January 28, 2006), WormBook, ed. The C. elegans Research Community, WormBook, doi/10.1895/wormbook.1.63.1, http://www.wormbook.org.

Copyright: © 2006 Robert E. Rhoads et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

§To whom correspondence should be addressed. E-mail: rrhoad@lsuhsc.edu

Current address: Departamento de Bioquimica, Facultad de Quimica, Universidad Nacional Autonoma de Mexico, 04510, Mexico DF, Mexico

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