The biosynthesis and biological function of diphthamide

Su, Xiaoyang; Lin, Zhewang; Lin, Hening

doi:10.3109/10409238.2013.831023

Cited by 71 publications

(64 citation statements)

References 58 publications

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“…This finding agrees with the known synthesis pathway that assigns DPH1, -2, and -4 to initial modification and DPH5 to diphthine synthesis (4)(5)(6). Loss of DPH1, -2, -4, and -5 cannot be compensated by other genes, even though mammalian genomes harbor extended gene families.…”

Section: Discussionsupporting

confidence: 88%

“…The diphthamide modification at His715 of human eEF2 (or at the corresponding position in other species) is conserved in all eukaryotes (3) and in archaeal counterparts. It is generated by proteins that are encoded by seven genes (4). Proteins encoded by dipthamide biosynthesis protein (DPH)1, DPH2, DPH3, and DPH4 (DNAJC24) attach a 3-amino-3-carboxypropyl (ACP) group to eEF2.…”

mentioning

confidence: 99%

“…Diphthamide synthesis was previously described in yeast and other eukaryotes (4)(5)(6). However, the "complete picture" is (with the exception of the yeast pathway) to a large portion is composed of observations made in different cell types on single genes.…”

mentioning

confidence: 99%

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Loss of diphthamide pre-activates NF-κB and death receptor pathways and renders MCF7 cells hypersensitive to tumor necrosis factor

Stahl¹,

Seidl²,

Ducret

et al. 2015

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

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The diphthamide on human eukaryotic translation elongation factor 2 (eEF2) is the target of ADP ribosylating diphtheria toxin (DT) and Pseudomonas exotoxin A (PE). This modification is synthesized by seven dipthamide biosynthesis proteins (DPH1-DPH7) and is conserved among eukaryotes and archaea. We generated MCF7 breast cancer cell line-derived DPH gene knockout (ko) cells to assess the impact of complete or partial inactivation on diphthamide synthesis and toxin sensitivity, and to address the biological consequence of diphthamide deficiency. Cells with heterozygous gene inactivation still contained predominantly diphthamide-modified eEF2 and were as sensitive to PE and DT as parent cells. Thus, DPH gene copy number reduction does not affect overall diphthamide synthesis and toxin sensitivity. Complete inactivation of DPH1, DPH2, DPH4, and DPH5 generated viable cells without diphthamide. DPH1ko, DPH2ko, and DPH4ko harbored unmodified eEF2 and DPH5ko ACP-(diphthine-precursor) modified eEF2. Loss of diphthamide prevented ADP ribosylation of eEF2, rendered cells resistant to PE and DT, but does not affect sensitivity toward other protein synthesis inhibitors, such as saporin or cycloheximide. Surprisingly, cells without diphthamide (independent of which the DPH gene compromised) were presensitized toward nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) and death-receptor pathways without crossing lethal thresholds. In consequence, loss of diphthamide rendered cells hypersensitive toward TNF-mediated apoptosis. This finding suggests a role of diphthamide in modulating NF-κB, death receptor, or apoptosis pathways.ADP-ribosylation of eEF2 | Pseudomonas exotoxin | diphtheria toxin | translation | DPH gene knockout

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Section: Discussionsupporting

confidence: 88%

mentioning

confidence: 99%

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Loss of diphthamide pre-activates NF-κB and death receptor pathways and renders MCF7 cells hypersensitive to tumor necrosis factor

Stahl¹,

Seidl²,

Ducret

et al. 2015

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

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“…In eukaryotic cells, several genes are known to be involved in the biosynthesis of diphthamide (31). We observed a significant enrichment of mutations in DPH1, DPH2, DPH4, and DPH7 (WDR85) (Fig.…”

Section: Mutations In the Diphthamide Biosynthetic Pathway Leads To Pmentioning

confidence: 53%

GPR107, a G-protein-coupled Receptor Essential for Intoxication by Pseudomonas aeruginosa Exotoxin A, Localizes to the Golgi and Is Cleaved by Furin

Tafesse

Guimarães

Maruyama

et al. 2014

Journal of Biological Chemistry

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Background: Bacterial toxins, including P. aeruginosa exotoxin A (PE), are valuable tools to dissect biological processes. Results: A genome-wide genetic screen identifies several novel host factors used by PE, including GPR107. Conclusion: Bacterial toxins can help identify novel host components involved in key intracellular trafficking steps. Significance: GPR107 may be a receptor that associates with G-proteins at the Golgi to regulate membrane transport.

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“…ADP-ribosylation of eEF2 occurs only when His715 of eEF2 contains a diphthamide. Diphthamide is generated by a pathway including seven diphthamide genes called DPH1-7 [38]. A pathway model has been described for yeast by Liu et al and Lin et al [39,40].…”

Section: Step 4-adp-ribosylation Of Eef2: Reduced or Altered Expressimentioning

confidence: 99%

Factors that Determine Sensitivity and Resistances of Tumor Cells Towards Antibody-Targeted Protein Toxins

Stahl¹,

Mueller

Pastan

et al. 2015

Resistance to Targeted Anti-Cancer Therapeutics

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Recombinant immunotoxins are composed of antibody-derived targeting entities fused to truncated toxins. Pseudomonas toxins inactivate eEF2 by ADPribosylation and are potent antitumoral agents in clinical development. The sensitivity of tumor cells towards such fusion proteins, and hence their therapeutic efficacy, is influenced by multiple factors: (i) access to tumor cells, (ii) target antigen binding and internalization, (iii) entry into the cytosol, (iv) enzymatic modification of the intracellular target eEF2, and (v) induction of apoptosis. Parameters that affect these steps and hence modulate sensitivity include: (i) protein stability and immunogenicity, (ii) presence, density and internalization of target antigen, (iii) cellular factors involved in processing, routing or translocation of the toxin, (iv) factors involved in diphthamide synthesis on eEF2, and (v) factors that influence cellular susceptibility towards apoptosis. This chapter describes sensitivity or resistance factors for Pseudomonas exotoxin -derived immunotoxins that were identified experimentally and/ or observed in clinical studies.

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The biosynthesis and biological function of diphthamide

Cited by 71 publications

References 58 publications

Loss of diphthamide pre-activates NF-κB and death receptor pathways and renders MCF7 cells hypersensitive to tumor necrosis factor

Loss of diphthamide pre-activates NF-κB and death receptor pathways and renders MCF7 cells hypersensitive to tumor necrosis factor

GPR107, a G-protein-coupled Receptor Essential for Intoxication by Pseudomonas aeruginosa Exotoxin A, Localizes to the Golgi and Is Cleaved by Furin

Factors that Determine Sensitivity and Resistances of Tumor Cells Towards Antibody-Targeted Protein Toxins

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