Organism | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | Q9H2P9 | - |
- |
Synonyms | Comment | Organism |
---|---|---|
Dph5 | - |
Homo sapiens |
General Information | Comment | Organism |
---|---|---|
malfunction | complete inactivation of DPH1, DPH2, DPH4, and DPH5 generated viable cells without diphthamide. Reduced growth rates are observed for all clones with completely inactivated DPH5. These contain ACP-modified eEF2, which occurs only in DPH5-deficient cells and not in other variants | Homo sapiens |
physiological function | the diphthamide on human eukaryotic translation elongation factor 2 is the target of ADP ribosylating diphtheria toxin and Pseudomonas exotoxin A. This modification is synthesized by seven dipthamide biosynthesis proteins (DPH1-DPH7) and is conserved among eukaryotes and archaea. MCF7 breast cancer cell line-derived DPH gene knockout cells are generated 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 contain predominantly diphthamide-modified eEF2 and are as sensitive to Pseudomonas exotoxin A and diphtheria toxin 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 generates viable cells without diphthamide. DPH1ko, DPH2ko, and DPH4ko harbor unmodified eEF2 and DPH5ko ACP-(diphthine-precursor)modified eEF2. Loss of diphthamide prevents ADP ribosylation of eEF2, renders cells resistant to Pseudomonas exotoxin A and diphtheria toxin, but does not affect sensitivity toward other protein synthesis inhibitors, such as saporin or cycloheximide. Cells without diphthamide (independent of which the DPH gene compromised) are presensitized toward nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-kappaB) and death-receptor pathways without crossing lethal thresholds. Loss of diphthamide renders cells hypersensitive toward TNF-mediated apoptosis | Homo sapiens |