Inhibition of translation by cytotrienin A—a member of the ansamycin family

Lindqvist, Lisa; Robert, Françis; Merrick, William C.; Kakeya, Hideaki; Fraser, Christopher S.; Osada, Hiroyuki

doi:10.1261/rna.2307710

Cited by 19 publications

(17 citation statements)

References 45 publications

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“…17,18 Recently, it has been shown that cytotrienin A inhibits eukaryotic protein synthesis by targeting translation elongation and interfering with eukaryotic elongation factor 1A function. 15 Consistent with this and our findings, 15,16 mycotrienin II and its structural derivatives inhibited cellular protein synthesis and cell-free translation. Nevertheless, the de novo protein synthesis in intact living cells (Figure 2a) was inhibited much more strongly by mycotrienin II than the cell-free translation ( Table 1).…”

Section: Discussionsupporting

confidence: 90%

“…The difference in sensitivity is in agreement with the observation that cytotrienin A inhibits cellular protein synthesis more strongly than the cell-free translation. 15 This may be because the cell-free translation systems contain larger amounts of proteins that bind to mycotrienin II or cytotrienin A (most likely eukaryotic elongation factor 1A) than living cells, and therefore higher concentrations of the compounds are required for the inhibition of translation.…”

Section: Discussionmentioning

confidence: 99%

“…15,16 To investigate whether mycotrienin (Figure 2b). When [ 3 H]L-leucine-labeled cell lysates were separated into acid-soluble supernatants and acid-insoluble precipitates, mycotrienin II inhibited the incorporation of radioactivity into the precipitates, but conversely increased the radioactivity incorporation into the supernatants (Figure 2c).…”

Section: Mycotrienin II Inhibits Cellular and Cell-free Translationmentioning

confidence: 99%

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Mycotrienin II, a translation inhibitor that prevents ICAM-1 expression induced by pro-inflammatory cytokines

et al. 2011

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Pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-a and interleukin-1a (IL-1a), trigger the activation of the transcription factor nuclear factor-jB, a molecule that induces the expression of a variety of genes, including intercellular adhesion molecule-1 (ICAM-1). Here, we report that mycotrienin II, a member of the triene-ansamycin group, inhibited the cell-surface ICAM-1 expression induced by TNF-a more strongly than that induced by IL-1a in human lung carcinoma A549 cells. Mycotrienin II was found to inhibit protein synthesis in intact living cells, as well as in cell-free translation systems. Among translation inhibitors tested, acetoxycycloheximide and anisomycin, but neither puromycin nor emetine, inhibited the TNF-a-induced ICAM-1 expression at lower concentrations than the IL-1a-induced ICAM-1 expression. Several compounds of the triene-ansamycin group (that is, mycotrienin I, trienomycin A, trierixin, quinotrierixin and quinotrierixin HQ) also inhibited ICAM-1 expression, as well as cell-free translation in a manner similar to mycotrienin II. These results indicate that mycotrienin II is a direct inhibitor of translation, thereby inhibiting ICAM-1 expression induced by pro-inflammatory cytokines.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Mycotrienin II Inhibits Cellular and Cell-free Translationmentioning

confidence: 99%

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Mycotrienin II, a translation inhibitor that prevents ICAM-1 expression induced by pro-inflammatory cytokines

et al. 2011

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“…The polysome profile was unchanged in cells treated with 4 compared to DMSO control ( Figure 2c , left panel), indicating that global translation initiation was not perturbed. To test for inhibition of translation elongation, we asked whether 4 could abrogate polysome runoff induced by the initiation inhibitor harringtonine ( Lindqvist et al, 2010 ). Similar to the known elongation inhibitor cycloheximide, pretreatment of cells with 4 completely blocked harringtonine-induced polysome depletion (2c, right panel).…”

Section: Resultsmentioning

confidence: 99%

Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex

Carelli

Sethofer

Smith

et al. 2015

eLife

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Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself. Using a ternatin photo-affinity probe, we identify the translation elongation factor-1A ternary complex (eEF1A·GTP·aminoacyl-tRNA) as a specific target and demonstrate competitive binding by the unrelated natural products, didemnin and cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are common targets for the evolution of cytotoxic natural products.DOI: http://dx.doi.org/10.7554/eLife.10222.001

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“…These were cytotrienin A (CytA), an ansamycin compound chemically distinct from DidB ( Fig. 4 C ) that we previously showed inhibits translation elongation specifically by interfering with eEF1A function ( Lindqvist et al, 2010 ) and cycloheximide (CHX), an elongation inhibitor that targets the ribosome ( Robert et al, 2009 ). CytA had similar effects to DidB in inducing nuclear accumulation of AID-GFP, but not GFP-APOBEC1, in HeLa cells, whereas CHX did not affect either protein ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Consecutive interactions with HSP90 and eEF1A underlie a functional maturation and storage pathway of AID in the cytoplasm

Methot

Litzler

Trajtenberg

et al. 2015

Journal of Experimental Medicine

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Methot et al. identify a mechanism for cytoplasmic retention of activation-induced deaminase (AID) in cells. Interactions of AID with Hsp90 and eEF1A proteins, both of which stabilize AID, promote sequential folding and retention of functional AID in the cytoplasm. Inhibition of the translation elongation factor eEF1A blocks its interaction with AID, which then accumulates in the nucleus, increasing class switch recombination and the generation of chromosomal translocation byproducts.

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Inhibition of translation by cytotrienin A—a member of the ansamycin family

Cited by 19 publications

References 45 publications

Mycotrienin II, a translation inhibitor that prevents ICAM-1 expression induced by pro-inflammatory cytokines

Mycotrienin II, a translation inhibitor that prevents ICAM-1 expression induced by pro-inflammatory cytokines

Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex

Consecutive interactions with HSP90 and eEF1A underlie a functional maturation and storage pathway of AID in the cytoplasm

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