Translation of eukaryotic cellular mRNA into protein is a complex process involving nearly 200 RNA and protein components interacting in a regulated fashion to ensure timely expression of genetic information(1) . Viruses often alter the host cell translational machinery to allow more efficient expression of virally encoded proteins. One of the most dramatic examples of this occurs upon picornaviral infection. The picornaviridae are small, icosohedral, positive-stranded RNA viruses of considerable clinical and veterinary importance, containing such members as poliovirus, rhinovirus, coxsackievirus, encephalomyocarditis virus, and foot-and-mouth-disease virus (FMDV)()(2, 3) . Infection of mammalian cells by most members of this family (all genera except cardioviruses and hepatitis A virus) impairs the ability of the host cell to translate capped mRNAs. Translation of the uncapped viral RNA still proceeds, however, by a cap-independent mechanism whereby ribosomes bind internally at specific sites on the viral RNAs(4, 5) . Thus, picornaviral infection results in the conversion of the predominant mode of translation initiation from cap-dependent to capindependent.

The host cell shutoff by rhinoviruses, enteroviruses, and aphthoviruses is thought to be mediated, at least in part, by the virally induced cleavage of a protein synthesis initiation factor, eIF4G()(6, 7, 8) . The loss of the ability to translate capped host mRNAs correlates with the conversion of eIF4G, detected immunologically, from a cluster of bands migrating on SDS-PAGE at 200-220 kDa to one of 100-130 kDa(6, 9) . This event is mediated by virally encoded proteases(10, 11) . The cleavage products of eIF4G detected in vivo are electrophoretically identical to those generated in vitro using highly purified recombinant forms of the viral proteases(12) . Although early evidence suggested that viral proteases played only an indirect role in eIF4G proteolysis(13, 14) , recent results support direct cleavage of eIF4G by virally encoded proteases(15, 16, 17) . However, the observation that eIF4G cleavage is not sufficient for total host cell shutoff in vivo(18, 19) suggests that additional events may play a role in the inhibition of cap-dependent translation.

eIF4G functions during initiation of translation through association with other members of the eIF4 group of translation factors (reviewed in (20, 21, 22) ). This group includes eIF4A, a 46-kDa bi-directional ATP-dependent helicase; eIF4B, a 70-kDa RNA-binding phosphoprotein which enhances eIF4A activity; eIF4E, a 25-kDa cap-binding phosphoprotein; and eIF4G itself, a 154-kDa phosphoprotein which can be isolated in complexes with eIF3, eIF4A, eIF4B, and eIF4E (23, 24, 25) . The best characterized of these complexes, eIF4F, consists of eIF4A, eIF4E, and eIF4G(23) . These polypeptides collectively recognize the mGTP-containing cap, unwind mRNA secondary structure, and facilitate binding of the 40 S ribosomal subunit.

The mechanism by which cleavage of eIF4G by picornaviral proteases contributes to an inhibition of cap-dependent translation is not understood, but some functions associated with eIF4F appear to be inactivated. Following poliovirus infection, cross-linking of eIF4 polypeptides to the cap structure is altered(9, 26, 27) . The pattern of cap-binding protein complexes recovered from infected cells is distinctly different from that of uninfected cells, suggesting that infection disrupts macromolecular complexes important for cap-dependent initiation(28, 29) . Since no alteration in other eIF3 or eIF4 polypeptides is apparent as a result of infection (6, 30, 31) , cleavage of eIF4G is thought to be responsible for the observed changes. This is supported by the fact that protein complexes containing intact eIF4G restore cap-dependent translation in extracts of infected cells(23, 32, 33) . Also, extracts of uninfected cells, when treated with purified viral proteases, lose their ability to translate capped mRNA, but addition of eIF4G-containing complexes restores this activity(8, 16) .

Not only does cleavage of eIF4G result in inactivation of some functions important for cap recognition, but there is also evidence that eIF4G may be important for cap-independent translation of viral RNAs. Addition of the eIF4F complex stimulates in vitro translation from picornaviral internal ribosome entry site sequences (34, 35, 36) . In contrast to cap-dependent initiation, cleavage of eIF4G by picornaviral proteases does not abrogate this stimulation but rather enhances it(16, 37, 38) . This suggests that eIF4G cleavage products play a direct role in cap-independent translation of viral RNAs(16, 37) .

Picornaviral proteases which cleave eIF4G fall into two separate classes. The 2A proteases of rhino- and enteroviruses are small thiol proteases with structural similarities to chymotrypsin and -lytic protease(39, 40, 41) . The primary cleavage site in rabbit eIF4G is Arg- Gly(15) , although a secondary site of unknown location has been suggested for the 2A protease of HRV2 (12) . The L protease of FMDV more closely resembles papain in structure (42) . It initially cleaves eIF4G at Gly-Arg and subsequently at multiple sites as yet unidentified(12) .

To understand better the role of eIF4G in cap-dependent and -independent initiation, we have examined the effect of proteolysis on the association of eIF4G with other initiation factors using recombinant viral proteases. We provide evidence that proteolysis of eIF4G at the primary site separates functional domains. We also report the localization of a second L protease cleavage site in eIF4G which further defines the binding region for eIF4E. These results suggest a model for the role of eIF4G cleavage products in translation of picornaviral RNA.

EXPERIMENTAL PROCEDURES

Materials

Antisera

Purification of Proteins

Reverse Phase Column Fractionation of eIF4G Cleavage Products

Generation of eIF4G Cleavage Products and mGTP-Sepharose Column Fractionation

Ultracentrifugal Sedimentation

Immunologic Procedures

Electrophoresis

RESULTS

Cleavage of eIF4G by L Protease

Figure 1: Time course of cleavage of eIF4G by L protease of FMDV. eIF4F was digested with recombinant L protease in the absence (lanes 1-7) or presence (lanes 8-14) of eIF3 as described under ``Experimental Procedures.'' Aliquots were removed at the indicated times and subjected to SDS-PAGE on 10% gels. A, silver-stained gel. B, immunoblot probed with anti-eIF4G antibodies. C, immunoblot probed with anti-eIF4G antibodies. The positions of standard proteins of the designated molecular masses ( 10) are indicated on the left. The positions of uncleaved eIF4G, the various cleavage products, eIF4A, and eIF4E are indicated on the right.

Figure 2: Summary of viral protease cleavage of eIF4G. Long rectangles indicate the 1402-amino acid residue rabbit eIF4G molecule or various cleavage products (proportional in length to the molecular masses of the fragments). Precise cleavage sites for 2A and L proteases in rabbit eIF4G are indicated by vertical lines through amino acid sequences. Approximate cleavage sites are indicated by lines through the rectangles. The locations in eIF4G of synthetic peptides used to generate antibodies are shown at the top with inclusive amino acid residue numbers (referring to the human sequence).

Further digestion with L protease caused the cp fragments to disappear and a heterogeneous cluster of fragments, designated cp, to appear (A, lanes 4-7). All members of the cp cluster arose simultaneously and therefore are likely to have resulted from cleavage of cp at a single site. The heterogeneity of cp is similar to that of cp and eIF4G itself, suggesting that the source of heterogeneity in eIF4G is localized to the cp region. Immunoblotting with an anti-eIF4G antibody detected a band with estimated molecular mass of 28 kDa, designated cp, which appeared simultaneously with the degradation of cp (B, lanes 2-4). With further digestion, some of cp was converted to smaller species termed cp (B, lanes 4-7). Immunoblotting with anti-eIF4G antibodies (B) and anti-eIF4G antibodies (data not shown) indicated that cp and cp contained amino acid residues 327-416, whereas cp did not. This permitted the orientation of cp, cp, and cp as shown in Fig. 2.

Further cleavage of the 103-kDa cp yielded a number of smaller fragments (cp-cp). The relative abundance and kinetics of appearance of the fragments together with immunoblotting with anti-eIF4G (Fig. 1C) and anti-eIF4G(12) antibodies is consistent with the following order of events. Initial cleavage of cp by L protease can occur at one of two nearby sites (see Fig. 2). This yields two overlapping polypeptides, cp (59 kDa) and cp (55 kDa), both of which can be seen in A, lanes 4-7, and both of which react with anti-eIF4G antibodies(12) . Secondary cleavage of cp generates cp (note gradual loss of cp and appearance of cp in Fig. 1A). When cp is initially cleaved to cp, the N-terminal half is represented by cp (40 kDa), which reacts with anti-eIF4G antibodies (C, lanes 3-7, and Fig. 2). When cp is initially cleaved to cp, the N-terminal half is represented by cp (45 kDa), which also reacts with anti-eIF4G antibodies (C, lanes 3-7). With longer times of incubation, cp and cp disappear simultaneous with the appearance of cp (35 kDa; C, lanes 4-7). Neither cp, cp, nor cp were recognized by anti-eIF4G (data not shown). These results indicate that cp and cp are derived from the C-terminal portion of cp and that cp, cp, and cp are derived from the N terminus (Fig. 2). Based on the SDS-PAGE-derived molecular masses, cp and cp approximately correspond to amino acid residues 480-886 and 887-1402 of rabbit eIF4G, respectively.

eIF3 is a multisubunit initiation factor that associates with eIF4F (29) . Previously we showed that eIF3 does not affect cleavage of eIF4G by 2A proteases from HRV2 and coxsackievirus serotype B4(15) . However, Wyckoff et al.(49, 50) have presented evidence that eIF3 is required for cleavage of eIF4G by poliovirus 2A protease. To determine if eIF3 affected either the rate or sites of cleavage of eIF4G by FMDV L protease, we repeated the time course in the presence of this factor at a concentration equimolar to that of eIF4F (Fig. 1, lanes 8-14). No cleavage of eIF4E or the various subunits of eIF3 was observed. The rate of appearance of the eIF4G cleavage products was unchanged except for a slight heterogeneity of the cp band; eIF3 caused a reduction in cp and the appearance of a new band 1 kDa smaller in size (cf.lanes 4-7 with lanes 11-14 in C). This suggests that eIF3 may block the accessibility of a protease site or expose a new one in this region of eIF4G.

The N-terminal Region of eIF4G Contains the eIF4E-binding Site

Figure 3: mGTP-Sepharose column fractionation of eIF4F treated with HRV2 protease 2A. eIF4F was incubated with 2A protease and fractionated on mGTP-Sepharose as described under ``Experimental Procedures.'' Aliquots of fractions were subjected to SDS-PAGE on an 8.5% gel. A, Coomassie Blue-stained gel. B, immunoblot probed with anti-eIF4G antibodies. C, immunoblot probed with anti-eIF4A. Lanes U and S represent eIF4F samples either untreated or treated with protease 2A, respectively, but not subjected to mGTP-Sepharose chromatography. FT, flow-through (unbound) fractions. mGTP, fractions eluted with mGTP.

A similar analysis of eIF4F treated with L protease was performed (Fig. 4). In this case, proteins in column fractions were resolved by SDS-PAGE and visualized by either silver staining (A) or immunoblotting with anti-eIF4G (B) or anti-eIF4G antibodies (C). (The fact that cp stains much more strongly than cp with silver has been documented previously(15) , but the reason is not known; it may be due to groups of charged amino acid residues observed in the cp portion of eIF4G (43) or posttranslational modifications which introduce hydrophylic or charged groups.) cp, fragments of cp, and eIF4A were not retained on the column but were found in the flow-through fractions (A and B, lanes 1-3). cp was also detected in the flow-through (A, lanes 1-3). Most of the cp, however, was retained on the column and co-eluted with eIF4E (A and C, lanes 6-8), indicating that the eIF4E-binding site is contained within this region of eIF4G. The fact that some of the cp and cp are found in the flow-through as well (lanes 1-3) may indicate dissociation from eIF4E during chromatography.

Figure 4: mGTP-Sepharose column fractionation of eIF4F treated with FMDV protease L. eIF4F was incubated with protease and fractionated on mGTP-Sepharose as in Fig. 3except that L protease was used instead of 2A protease (see ``Experimental Procedures''). A, silver-stained gel. B, immunoblot of the same gel probed with anti-eIF4G antibodies. C, immunoblot of the same gel probed with anti-eIF4G antibodies.

In order to define more precisely the region of eIF4G that binds to eIF4E, we determined the L protease cleavage site at the cp/cp junction. Fragments of eIF4G produced by a brief digestion with L protease were subjected to reverse phase HPLC on a C4 column (Fig. 5). The peaks in fractions 40-50 contained cp and cp and were well resolved from the peak in fractions 51-56, which contained cp. Although cp and cp eluted in the same general region, it was possible to resolve the majority of the cp (fractions 44-47) from the cp (fractions 40-43). cp was subjected to N-terminal sequence analysis by automated Edman degradation (Table 1). Alignment of the resultant sequence with the rabbit polypeptide sequence determined by cDNA cloning indicated that L protease cleaves at Lys-Arg, which corresponds to Lys-Arg in human eIF4G. This indicates that the eIF4E-binding site lies between amino acid residues 319 and 479.

Figure 5: Purification of the cp fragment by reverse phase HPLC. L protease-treated eIF4F was fractionated by reverse phase HPLC on C4 as described under ``Experimental Procedures.'' Equal aliquots from the indicated fractions were subjected to SDS-PAGE on 10% gels. A, elution pattern of cp, cp, and cp. B, silver-stained gel of column fractions. C, immunoblot of the same gel probed with anti-eIF4G antibodies.

Knowledge of this site allows a comparison of the true molecular masses of cp and cp to the SDS-PAGE-derived masses. The calculated molecular mass for cp based on this cleavage site is 32.5 kDa, but the observed mobility on SDS-PAGE for cp bands is 80-100 kDa. Also, cp is heterogeneous, whereas cp is not (Fig. 5B). cp migrates as a 28-kDa polypeptide despite its true molecular mass of 18 kDa. This indicates that cp is responsible for most of the heterogeneity and aberrant mobility of eIF4G.

Knowledge of the cp/cp junction also allows one to make conclusions about further cleavage products of cp. The size difference between cp and cp is 2-4 kDa, but both are recognized by the anti-eIF4G antibodies ( Fig. 1and Fig. 5). This epitope is located only nine amino acid residues (1.2 kDa) from the N terminus of cp. The fact that cp is recognized by anti-eIF4G antibodies suggests that it has the same N terminus as cp and hence that the cleavage converting cp to cp is at its C terminus (see Fig. 2).

The C-terminal Region of eIF4G Contains the eIF4A- and eIF3-binding Sites

The eIF3eIF4F complex was isolated, digested with either 2A or L protease, and the products subjected to sedimentation analysis (Fig. 6). The sedimentation of eIF3 was indicated by immunoreactivity of the 110-kDa eIF3 subunit. In the absence of protease, eIF4G and eIF3 sedimented at approximately 18 S with the eIF3eIF4F complex (A, lanes 6-9). The majority of the eIF4A (70%) co-sedimented with this complex as well, although some apparently dissociated during sedimentation. Cleavage of eIF4G disrupted the eIF3eIF4F complex. When eIF4G was cleaved by 2A protease, the two fragments of eIF4G did not co-sediment. Rather, all of the cp sedimented near the top of the gradient (B, lanes 1-2), whereas all of the cp and most (75%) of the eIF4A co-sedimented with eIF3 (lanes 6-9). This indicates that cp and eIF4A remain associated with eIF3 after 2A cleavage of eIF4G, but cp does not.

Figure 6: Ultracentrifugal fractionation of the protease-treated eIF3eIF4F complex. The eIF3eIF4F complex was incubated in the absence (A) or presence of the 2A (B) or L (C) proteases, layered onto 15-30% sucrose gradients, and centrifuged as described under ``Experimental Procedures.'' Gradients were fractionated and aliquots subjected to SDS-PAGE on 8.5% gels. 3, immunoblot probed with anti-eIF3 antibodies; 4A, immunoblot probed with anti-eIF4A antibodies; 4G, cp, cp, and cp, immunoblot probed with anti-eIF4G antibodies; cp, immunoblot probed with anti-eIF4G antibodies; cp, immunoblot probed with anti-eIF4G antibodies. Lane S represents the starting material which was layered onto each gradient. Fraction 1 corresponds to the top of the gradient.

Limited digestion of eIF4G by L protease disrupted its interaction with both eIF4A and eIF3 (C). Whereas all remaining intact cp and some eIF4A still co-sedimented with eIF3 (lanes 5-8), most of the eIF4A (80%), as well as all of the cp and cp, shifted to the top of the gradient (lanes 1-4). The proportion of eIF4A at the top of the gradient was approximately equal to the proportion of cp cleaved. Longer digestion with L protease resulted in complete cleavage of cp and all of the eIF4A shifting to the top of the gradient (data not shown). The cp fragment co-sedimented with eIF3 (lanes 6 and 7), whereas cp and cp were released and sedimented near the top of the gradient (data not shown). These results suggest that the eIF3-binding site is located within cp.

Since eIF4A co-sedimented with cp, the eIF4A binding site is likely to be contained within this region. The fact that eIF4A shifts to the top of the gradient when cp is further digested with L protease (C) could mean that either eIF4A is free or is bound to a fragment of eIF4G which has shifted to the top of the gradient, e.g. cp or cp. To determine whether eIF4A has affinity for cp or cp, we covalently attached purified anti-eIF4G antibody to agarose beads and used this immunoaffinity resin to test for physical association between eIF4A and fragments of eIF4G. L protease was incubated with either eIF4A alone (Fig. 7, lane 1) or eIF4A mixed with eIF4F (lanes 2 and 3), the reactions subjected to immunoadsorption, and the bound fractions analyzed (lanes 4-6). (eIF4A was added to the eIF4F preparation because eIF4F prepared by the method of Lamphear and Panniers (25) is substoichiometric for eIF4A.) The immobilized antibody bound cp, cp, and cp as expected (A, cf.lanes 2 and 3 with lanes 5 and 6); the strong band below cp migrating at 50 kDa is the highly immunoreactive IgG heavy chain, which probably results from insufficient removal of the immunoaffinity resin from eluted samples). eIF4A alone was not bound to the immunoaffinity resin (B, lane 4) unless eIF4G fragments were present (B, lanes 5 and 6). In a similar experiment in which the digestion with L protease was continued until all of the cp was converted to cp, eIF4A was also retained on the immunoaffinity resin (data not shown), indicating that the 4 kDa which is removed from cp by the secondary L protease cleavage does not contain the eIF4A binding site.

Figure 7: Immunoadsorption of L protease-treated eIF4F with immobilized anti-eIF4G antibodies. eIF4A (2 µg, lanes 1 and 4) or eIF4A plus eIF4F (2 µg each, lanes 2, 3, 5, and 6) were incubated with L protease in 50 µl of buffer D. Aliquots (5 µl) were removed for gel analysis (lanes 1-3) and the remainder subjected to immunoadsorption on an anti-eIF4G resin as described under ``Experimental Procedures.'' The eluate (bound fraction) was then analyzed by SDS-PAGE on 8.5% gels (lanes 4-6). A, 12 µg of protease were used and incubation was for either 30 min (lanes 1, 2, 4, and 5) or 90 min (lanes 3 and 6). The immunoblot was probed with anti-eIF4G antibodies. The band migrating at 50 kDa in lanes 5 and 6 is rabbit IgG heavy chain, which contaminates some of the eluates. B, same as A except the immunoblot was probed with anti-eIF4A antibodies. In this case the IgG heavy chain does not react, since the secondary antibody used was goat anti-mouse. C, same as A except incubation with protease was for 30 min, 3 µg of protease were used in lanes 1, 2, 4, and 5, and 6 µg were used in lanes 3 and 6. Also, the immunoblot was probed with anti-eIF4G antibodies.

As a control, the anti-eIF4G antibody was used to test whether cp, cp, or cp were bound to the immunoaffinity resin. If this were the case, e.g. that cp remained bound to cp after proteolytic cleavage of cp, it would not be possible to distinguish whether eIF4A were bound to cp or cp. The experiment indicated that cp, cp, or cp, though detectable in the starting material (Fig. 7C, lanes 2 and 3), was not retained by the resin (lane 5). (Contamination by the IgG heavy chain did not permit analysis of cp in lane 6, but cp or cp were clearly absent.) cp, on the other hand, which contains the epitope for both anti-eIF4G and anti-eIF4G antibodies, was detected in the bound fractions (Fig. 7C, lanes 5 and 6). Thus, the immobilized anti-eIF4G antibody selectively adsorbs cp and cp, but not cp, cp, or cp. In a similar experiment using anti-eIF4G antibodies, it was determined that cp did not bind to the immunoaffinity resin (data not shown). In summary, these results indicate that there is a binding site for eIF4A in the cp fragment of eIF4G.

DISCUSSION

Previous studies have established that eIF4G can form complexes with initiation factor polypeptides whose activities are associated with each of the events necessary for recruitment of host cell mRNA for translation. These events are cap recognition, a property of eIF4E (reviewed in (52) ); ATP-dependent unwinding of mRNA secondary structure, which is a property of eIF4A alone but one which is greatly enhanced by the presence of eIF4B and eIF4G(53, 54) ; and ribosome binding, which requires eIF3(55, 56, 57) . Purification of a high salt ribosomal wash by gel filtration (23) or mGTP-Sepharose chromatography (25) leads to co-elution of eIF4A, eIF4B, eIF4E, eIF4G, and eIF3 in a large macromolecular complex. The present study indicates that treatment with proteases which have high specificity for eIF4G separates these major functional activities into two complexes, one containing the cap recognition function and one containing the helicase and ribosome binding functions (Fig. 3, 4, 6, and 7). In vivo, the 2A and L proteases appear to carry out only the cleavage event which generates cp and cp(12) . Therefore, the activities of these fragments are most relevant to viral replication. However, further proteolysis by L protease in vitro, again specific for eIF4G, results in the separation of the ribosome binding function (eIF3) and the helicase function (eIF4A; Fig. 6). This suggests that these three functional activities of initiation factors involved in mRNA recruitment (cap binding, RNA helicase, and ribosome binding) are brought together principally through an interaction with eIF4G rather than with each other.

cp is the region of eIF4G responsible for binding eIF4E, representing amino acid residues 1-486 of rabbit eIF4G in the case of 2A protease cleavage (1-479 in the case of L protease). Finer mapping with L protease narrows this region to amino acids 319-479. The criterion in either case is retention on mGTP-Sepharose. Previously it was reported that poliovirus-induced cleavage products of eIF4G, as detected by a monoclonal antibody, were retained on cap-analog columns, but the location of the epitope was unknown (27, 28, 29) . With the availability of antibodies to defined regions of eIF4G, it is now possible to conclude that the monoclonal antibody used earlier recognizes the same cleavage products as antipeptide antibodies against amino acid residues 327-416(43) . The validity of mGTP-Sepharose retention as a basis for assigning the eIF4E-binding region to cp is reinforced by the observation that cp in the absence of eIF4E is not retained on mGTP-Sepharose(28) .

cp, representing amino acids 480-1402, is the region of eIF4G which binds to eIF4A and eIF3, as demonstrated by co-sedimentation (Fig. 6) and immunoadsorption (Fig. 7). cp contains the eIF3-binding site, based primarily on co-sedimentation, but also supported by the observation that eIF3 alters cleavage within cp (Fig. 1C). cp contains the eIF4A binding site, since both eIF4A and cp are released from eIF3 by L protease and co-sediment (Fig. 6C). Also, eIF4A specifically binds to the anti-eIF4G affinity resin, but only in the presence of cp or larger fragments containing cp (Fig. 7B).

Putting these two sets of data together suggests a domain model for eIF4G wherein the cap recognition function is in the N-terminal one-third of the molecule and the unwinding and ribosome binding functions are in the C-terminal two-thirds (Fig. 8). The region separating the N- and C-terminal domains may be a flexible hinge or loop which is more exposed to proteases. In support of this prediction, analysis of secondary structure motifs suggests that this region has a high probability of -turns(58) . Furthermore, a synthetic peptide based on a different portion of the eIF4G sequence is cleaved by HRV2 protease 2A(17) , but this site is not cleaved in intact eIF4G(15) , suggesting that it is in a region of the molecule which is not as accessible as the putative hinge region. Finally, fragments of eIF4G similar in size to cp are observed upon raising Ca levels in extracts of uninfected cells, suggesting that the junction between cp and cp is more susceptible to normal intracellular proteases (59) .

Figure 8: A domain model for eIF4G in cap-dependent and -independent initiation of translation. A model for the involvement of eIF4G (4G) in cap-dependent and -independent initiation is shown, based on the binding sites on eIF4G for eIF4E (E), eIF4A (A), and eIF3 (3). A, cap-dependent initiation. Only one of the current models for cap-dependent initiation, the stepwise assembly model, is depicted (see text). eIF4E binds to the mRNA cap, whereas eIF4G binds to eIF3 on the 43 S initiation complex. The protein-protein interaction between eIF4E and eIF4G brings the mRNA to the ribosome and the unwinding machinery, represented by eIF4A. The wavy portion of mRNA indicates secondary structure. The ability of eIF4G to bind eIF4A, eIF3, and eIF4E is critical for mediating cap-dependent joining of mRNA to the ribosome and positioning of the RNA helicase at the 5`-end of the mRNA. B, cap-independent initiation. During replication of rhino-, entero-, and aphthoviruses, cleavage of eIF4G separates the eIF4E-binding domain (cp) from the eIF3- and eIF4A-binding domain (cp). This produces an altered 43 S initiation complex (*), disrupting the ability of eIF4G to mediate cap-dependent recruitment of RNA to the ribosome but not altering the binding of cp to the ribosome or helicase activity required for internal initiation.

Is such a domain model compatible with current ideas about cap-dependent initiation? Two models for the mRNA-binding step of initiation have been proposed, here referred to as the stepwise assembly model and the preformed complex model. Recruitment of capped mRNAs requires the coupling of cap recognition, unwinding, and scanning. The models differ primarily in which of these functions occur on the ribosome. The division of eIF4G into functional domains, however, is compatible with either model. The stepwise assembly model states that eIF4E first recognizes the cap as a free polypeptide, i.e. not in the eIF4F complex, whereas eIF4G is present in the 43 S initiation complex prior to mRNA recruitment, bound to eIF3 ((60) ; see Fig. 8). eIF4A, although largely found in the postribosomal supernatant, may also be bound to eIF4G and hence also be present in the 43 S initiation complex. The joining of eIF4E to eIF4G brings mRNA to the 40 S ribosomal subunit and to the unwinding machinery. In this model, the cp region would serve to anchor eIF4G to the ribosome via eIF3 and provide a binding site for eIF4A (and possibly eIF4B as well), whereas the cp domain would provide a flexible arm to receive the incoming eIF4E:mRNA complex (Fig. 8A). Cleavage of eIF4G by viral proteases would permit eIF4E to bind the cap and the eIF4EmRNA complex to bind cp (Fig. 8B, upper portion), but these events would occur apart from the unwinding machinery and the 40 S ribosomal subunit. Hence, no recruitment of capped mRNA to the ribosome would result. The preformed complex model states that eIF4F exists prior to formation of any complexes between mRNA, initiation factors, or ribosomes(3, 21, 22, 61) . This eIF4F complex recognizes the cap of free mRNA and unwinds its secondary structure. When a sufficiently long stretch of secondary structure is unwound, the 40 S ribosomal subunit binds and begins scanning. A domain structure for eIF4G as proposed here would suggest that eIF4E, bound to the cp region of eIF4G, first recognizes the cap and directs the mRNA to the unwinding machinery which is bound to the cp region. Cleavage of eIF4G by viral proteases would yield separate complexes capable of cap recognition and unwinding, but since unwinding would not be directed to the 5`-end of the mRNA, ribosome binding to single-stranded RNA would be frequently unproductive.

Is such a domain model for eIF4G compatible with current ideas about cap-independent initiation? Translation of picornaviral RNA requires eIF4A, and inactive variants of eIF4A have a dominant negative effect on translation of both capped and picornaviral mRNAs(36) . This inhibition can be overcome by the addition of normal eIF4A, but the addition of eIF4F is six times more effective, underscoring the importance of eIF4G for unwinding. Binding of picornaviral RNA to the ribosome requires an internal ribosome entry site sequence (reviewed in (62) ). As eIF3 is involved in mRNA binding to ribosomes (see above), it must be presumed that translation of picornaviral RNA requires eIF3. In summary, translation of picornaviral RNA requires factors involved in unwinding (eIF4A, eIF4B) and ribosome binding (eIF3) but not cap recognition (eIF4E). Cleavage of eIF4G by picornaviral proteases separates the functions required for cap-independent translation (those attached to cp) from those which are not (those attached to cp; see Fig. 8B). It is interesting in this light that the primary cleavage sites in eIF4G for 2A protease (15) and L protease (12) are only seven amino acid residues apart, despite the fact that the proteases are structurally distinct and that the amino acid sequences surrounding the cleavage sites bear little similarity. Thus, there has been evolutionary conservation among the entero-, rhino-, and aphthoviruses of function (separation of cp from cp) rather than recognition of a specific amino acid sequence.

cp is thus likely to contain the functions required for cap-independent initiation. A binding site for eIF3 in cp permits attachment to the ribosome. Consistent with this, we have observed that cp sediments with ribosomes in a micrococcal nuclease-treated rabbit reticulocyte lysate (data not shown). A binding site for eIF4A in cp suggests that unwinding functions can take place in the absence of cp. The unwinding activity eIF4A is greatly enhanced when it is present in the eIF4F complex(53, 54) ; based on the location of the eIF4A binding site, it is likely that this stimulatory activity of eIF4G resides in cp. Also, there is a proposed RNA-binding region in eIF4G which is within cp(63) , and this region may be important for recruitment of mRNAs to the ribosome or stabilization of mRNA-ribosome interactions during translation of cellular and viral mRNAs. The proposed requirement of cp for internal initiation may explain a paradoxical observation: picornavirus infection ``inactivates'' eIF4F(6, 64) , yet eIF4F has been shown to stimulate internal cap-independent initiation from viral sequences(34, 35, 65) . The proposed domain model would state that the added eIF4F is supplying functions contained in the cp region which are needed for cap-independent translation; eIF4F is ``inactivated'' by 2A or L protease only with respect to cap-dependent translation. Based on this consideration, one would predict that cp alone would stimulate cap-independent initiation through its eIF3, eIF4A, and possibly RNA binding properties.

FOOTNOTES

*

This work was supported by Research Grant GM20818 from the National Institute of General Medical Sciences, National Institutes of Health (to R. E. R.) and a grant from the Austrian Science Foundation (to T. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

To whom correspondence should be addressed.

()

The abbreviations used are: FMDV, foot-and-mouth disease virus; eIF, eukaryotic initiation factor; HPLC, high pressure liquid chromatography; HRV2, human rhinovirus serotype 2; MOPS, 3-(N-morpholino)propanesulfonic acid; PAGE, polyacrylamide gel electrophoresis.

()

The names of initiation, elongation, and termination factors were revised on April 8, 1995 by an expert panel, Dr. Marianne Grunberg-Manago, Convener, appointed by the IUBMB Nomenclature Committee. The new names are used in the present article. eIF4G was formerly referred to as either p220, eIF-4, or eIF-4F.

ACKNOWLEDGEMENTS

Note Added in Proof-Mader et al. (Mader, S., Lee, H., Pause, A., and Sonenberg, N.(1995) Mol. Cell. Biol., in press) have recently shown in agreement with our results that eIF4E interacts with the N-terminal portion of eIF4G. They have mapped the eIF4E-binding region to within amino acids 409-457 and have identified a conserved motif between amino acids 413-424 that is important for the interaction.

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