Functional characterization of IRESes by an inhibitor of the RNA helicase eIF4A

Bordeleau, Marie-Ève; Mori, Ayaka; Oberer, Monika; Lindqvist, Lisa; Chard, Louisa S.; Higa, Tatsuo; Belsham, Graham J.; Wagner, Gerhard; Tanaka, Junichi; Pelletier, Jerry

doi:10.1038/nchembio776

Cited by 329 publications

(362 citation statements)

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“…Although the detailed binding sites of these chemicals are not characterized, hippuristanol is known to bind to the CTD of eIF4A and impairs the RNA-binding activity of eIF4A, whereas pateamine A inhibits eIF4A-eIF4G association (18,19). Our structure reveals that PDCD4 binds and regulates eIF4A differently from these compounds; PDCD4 recognizes both sides of the interdomain cleft of eIF4A (Fig.…”

Section: Implication Of the Two Different Binding Modes In The Functimentioning

confidence: 98%

“…The two marine natural products, pateamine A and hippuristanol, which regulate the activities of eIF4A, have recently been identified (18,19). Although the detailed binding sites of these chemicals are not characterized, hippuristanol is known to bind to the CTD of eIF4A and impairs the RNA-binding activity of eIF4A, whereas pateamine A inhibits eIF4A-eIF4G association (18,19).…”

Section: Implication Of the Two Different Binding Modes In The Functimentioning

confidence: 99%

See 1 more Smart Citation

Crystal structure of the eIF4A–PDCD4 complex

Chang

Cho

Sohn

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

103

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Tumor suppressor programmed cell death protein 4 (PDCD4) inhibits the translation initiation factor eIF4A, an RNA helicase that catalyzes the unwinding of secondary structure at the 5 -untranslated region of mRNAs and controls the initiation of translation. Here, we determined the crystal structure of the human eIF4A and PDCD4 complex. The structure reveals that one molecule of PDCD4 binds to the two eIF4A molecules through the two different binding modes. While the two MA3 domains of PDCD4 bind to one eIF4A molecule, the C-terminal MA3 domain alone of the same PDCD4 also interacts with another eIF4A molecule. The eIF4A-PDCD4 complex structure suggests that the MA3 domain(s) of PDCD4 binds perpendicular to the interface of the two domains of eIF4A, preventing the domain closure of eIF4A and blocking the binding of RNA to eIF4A, both of which are required events in the function of eIF4A helicase. The structure, together with biochemical analyses, reveals insights into the inhibition mechanism of eIF4A by PDCD4 and provides a framework for designing chemicals that target eIF4A.translation inhibition ͉ tumor suppressor ͉ RNA helicase ͉ domain closure ͉ MA3 domain P rogrammed cell death protein 4 (PDCD4) is a translation inhibitor that suppresses neoplastic transformation in cultured cells and transgenic mice (1-3). Loss or reduced expression of PDCD4 has been implicated in the development and progression of a variety of aggressive human cancers (4-6). PDCD4 is regulated by the S6K1 kinase and the SCF ␤TRCP ubiquitin ligase in response to the activation of the mTOR pathway by mitogens, and the controlled degradation of PDCD4 is essential for efficient protein synthesis and consequently for cell growth and proliferation (7).PDCD4 is believed to perform its tumor suppressor function primarily through interaction with eIF4A and eIF4G, which are components of mRNA-binding complex eIF4F (8). eIF4A is a DEAD-box RNA helicase, with two domains, that unwinds the secondary structures in 5Ј-untranslated region (UTR) and cap of mRNA and thereby facilitates ribosome scanning (8). eIF4G is an adaptor protein that coordinates assembly of translation factors and the small ribosomal subunit (8). PDCD4 is believed to inhibit cap-dependent translation by directly inhibiting the helicase activity of eIF4A or by competing with eIF4G for binding to eIF4A and preventing assembly into a eukaryotic initiation complex, eIF4F, or both (1, 9, 10).PDCD4 is formed with the two MA3 domains at its middle (mMA3) and C-terminal regions (cMA3) (9, 11-13). Mutational and NMR binding analysis have shown that PDCD4 uses both MA3 domains to interact with eIF4A and prevents translation (9, 10). However, other studies have demonstrated that the cMA3 domain alone is sufficient for the inhibition of RNA helicase and translation (12). The interactions between eIF4A and PDCD4 have been analyzed in several mutational and NMR mapping studies (1, 9, 10). Nevertheless, it is unclear from these studies how PDCD4 inhibits eIF4A at the molecular level. To elucidate ...

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Section: Implication Of the Two Different Binding Modes In The Functimentioning

confidence: 98%

Section: Implication Of the Two Different Binding Modes In The Functimentioning

confidence: 99%

Crystal structure of the eIF4A–PDCD4 complex

Chang

Cho

Sohn

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

103

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“…Geldanamycin targets Hsp90 and interferes with the folding of PV capsid, but not with RNA replication, probably in cooperation with Hsp70 (Geller et al, 2007;Macejak & Sarnow, 1992). Hippuristanol, a natural product of the coral Isis hippuis, inhibits RNA binding of eIF4A and delays the appearance of virus proteins in PV replication for 2 h (Bordeleau et al, 2006). Calpain inhibitors inhibit the replication of echovirus 1, possibly by targeting the activities of calpain 1 and 2 (Upla et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Cellular kinase inhibitors that suppress enterovirus replication have a conserved target in viral protein 3A similar to that of enviroxime

Arita

Wakita

Shimizu

2009

Journal of General Virology

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Previously, we identified a cellular kinase inhibitor, GW5074, that inhibits poliovirus (PV) and enterovirus 71 replication strongly, although its target has remained unknown. To identify the target of GW5074, we searched for cellular kinase inhibitors that have anti-enterovirus activity similar or related to that of GW5074. With this aim, we performed screenings to identify cellular kinase inhibitors that could inhibit PV replication cooperatively with GW5074 or synthetically in the absence of GW5074. We identified MEK1/2 inhibitors (SL327 and U0126), an EGFR inhibitor (AG1478) and a phosphatidylinositol 3-kinase inhibitor (wortmannin) as compounds with a cooperative inhibitory effect with GW5074, and an Akt1/2 inhibitor (Akt inhibitor VIII) as a compound with a synthetic inhibitory effect with MEK1/2 inhibitors and AG1478. Individual treatment with the identified kinase inhibitors did not affect PV replication significantly, but combined treatment with MEK1/2 inhibitor, AG1478 and Akt1/2 inhibitor suppressed the replication synthetically. The effect of AG1478 in this synthetic inhibition was compensated by other receptor tyrosine kinase inhibitors (IGF-1R inhibitor II and Flt3 inhibitor II). We isolated mutants resistant to Flt3 inhibitor II and GW5074 and found that these mutants had crossresistance to each treatment. These mutants had a common mutation in viral protein 3A that results in an amino acid change at position 70 (Ala to Thr), a mutation that was previously identified in mutants resistant to a potent anti-enterovirus compound, enviroxime. These results suggest that cellular kinase inhibitors and enviroxime have a conserved target in viral protein 3A to suppress enterovirus replication. INTRODUCTIONThe genus Enterovirus consists of at least ten species of non-enveloped viruses with a single-stranded, positivesense genomic RNA that belong to the family Picornaviridae. Enterovirus infection is mostly asymptomatic, but sometimes causes severe neurological symptoms exemplified by poliomyelitis. In infection by poliovirus (PV), which is the causative agent of poliomyelitis and belongs to the species Human enterovirus C, motor neurons are the major target for neurovirulence (Bodian, 1949). Enterovirus 71 (EV71), another neurotropic enterovirus belonging to the species Human enterovirus A, is a causative agent of hand, foot and mouth disease and herpangina, but sometimes causes severe neurological diseases, such as brainstem encephalitis and poliomyelitis-like paralysis (Chumakov et al., 1979;McMinn, 2002;Wang et al., 2003). EV71 causes fatal pulmonary oedema and pulmonary haemorrhage in young children by destruction of the vasomotor and respiratory centres in the brainstem Ho et al., 1999;Huang et al., 1999;Komatsu et al., 1999;Lum et al., 1998;Wang et al., 1999). For PV, live-attenuated and inactivated vaccines have been established and are currently being used for global eradication of poliomyelitis (Sabin, 1965;Salk et al., 1954). However, there is no effective therapeutic means for vaccine-associated...

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“…The rocaglamides (including silvestrol) act as eIF4A inhibitors and have been shown to exert antitumour activity both in vitro and in vivo. [8][9][10] More recent studies have shown that the natural product inhibitor hippuristanol (isolated from the coral Isis hippuris 8 is capable of reversing drug resistance in tumours engineered to be dependent on PI3K/AKT/mTOR signalling. 11 Moreover, it has been shown in cell lines and in xenographs derived from patients with malignant melanoma that formation of eIF4F complex is associated with resistance to anti-BRAF(V600) inhibitors.…”

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confidence: 99%