Table 1.
Known ribotoxic stress agents and their mechanism of action
| Ribosomal target | Cellular effect | |
|---|---|---|
| Translation inhibitors | ||
| Anisomycin | Prevents peptide bond formation at PTC, 60S A-site (52) Interacts with domain V of 28S rRNA | p38 and JNK activation (47) in a ZAKα dependent manner (66,70,72) and leads to transcription and secretion of IL-8 via ZAK/p38 signaling axis (48,71) |
| Cycloheximide | Inhibits translocation via interactions with the 60S E-site | p38 and JNK activation in a ZAKα dependent manner (47,72) |
| Lactimidomycin | Blocks initiation by inhibiting first round of translocation at the 60S E-site (52) | p38 and JNK activation in a ZAKα dependent manner (72) |
| Harringtonine | Blocks initiation by inhibiting first peptide bond formation at PTC, 60S A-site (153) | p38 and JNK activation in a ZAKα dependent manner (72) |
| Deoxynivalenol / trichothecene toxins | Prevents peptide bond formation at PTC, 60S A-site | p38 and JNK activation (154) |
| Onnamide A | Inhibits protein translation measured by [3H]-leucine incorporation (62) | p38 and JNK activation (62) |
| Theopederin B | Inhibits protein translation measured by [3H]-leucine incorporation (62) | p38 and JNK activation (62) |
| Ribotoxins | ||
| Ricin Ricinus communis | Depurination of adenine in the sarcin/ricin loop located in domain VI of 28S rRNA (155) | p38 and JNK activation and IL8 production in a ZAKα dependent manner (47,71,72,77) Ricin-induced cell death is mediated by ZAK (71) Zak-/- mice have lower duodenal pathology score than wt mice following oral ricin intoxication (77) |
| Shiga toxin Shigella dysenteriae Escherichia Coli | Depurination of adenine in the sarcin/ricin loop located in domain VI of 28S rRNA (155) | p38 and JNK activation (50) in a ZAK dependent manner (71) N-glycosidase activity of Stx1 is required for p38 and JNK activation (49) Stx at high doses induce cell death via p38 and ZAK (49,71) |
| α-sarcin Aspergillus giganteus | Cleavage of phosphodiester bond in the sarcin/ricin loop (53) | p38 and JNK activation (47) |
| Chemotherapeutics | ||
| Doxorubicin | Inhibits protein translation measured by [3H]-leucine incorporation (61) | p38 and JNK activation and cell death in a ZAK dependent manner (61,94) Upregulation of transcription and secretion of inflammatory cytokines IL-6 and CXCL1 via p38/ZAK (58,94) |
| Daunorubicin | Structurally similar to doxorubicin (61) | p38 and JNK activation and cell death in a ZAK dependent manner (61) |
| UV-radiation | ||
| UV-B and UV-C | Induce rRNA lesions at domain V and VI of 28S rRNA (63) | p38 and JNK activation (63) in a ZAKα dependent manner (66,70) Sorafenib, a multi-kinase inhibitor, repress UV-induced apoptosis via ZAK and JNK (76) |
| UV-damaged mRNA | Activation of ZAKα, p38 and JNK in cells after transfection with UV-irradiated mRNA (66) |