ArticleProceedings of the National Academy of Sciences of the United States of America2015
Loss of diphthamide pre-activates NF-κB and death receptor pathways and renders MCF7 cells hypersensitive to tumor necrosis factor.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 55 citations in OpenAlex.
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- Multi-proteomic profiling of the varicella-zoster virus-host interface reveals host susceptibilities to severe infection.Nature microbiology · 2025Article
- DNAJC24 suppresses breast cancer malignancy and serves as a prognostic biomarker.Cancer cell international · 2025Article
- Diphthamide synthesis is linked to the eEF2-client chaperone machinery.FEBS letters · 2025Article
- Genome-wide screening in human embryonic stem cells identifies genes and pathways involved in the p53 pathway.Molecular medicine (Cambridge, Mass.) · 2025Article
- DPH2 is a biomarker associated with cell death, immunity and prognosis based on pan-cancer analysis.Discover oncology · 2025Article
- Elongation factor 2 in cancer: a promising therapeutic target in protein translation.Cellular & molecular biology letters · 2024Review
- Loss of Diphthamide Increases DNA Replication Stress in Mammalian Cells by Modulating the Translation of RRM1.ACS central science · 2024Article
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- Diphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects.Nature communications · 2024Article
- Functional Integrity of Radical SAM Enzyme Dph1•Dph2 Requires Non-Canonical Cofactor Motifs with Tandem Cysteines.Biomolecules · 2024Article
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- Yeast geneMicrobial cell (Graz, Austria) · 2023Article
- DPH1 and DPH2 variants that confer susceptibility to diphthamide deficiency syndrome in human cells and yeast models.Disease models & mechanisms · 2023Article
- Translational fidelity and growth of Arabidopsis require stress-sensitive diphthamide biosynthesis.Nature communications · 2022Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 3 countries.
Funding
Abstract
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.
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