Can trichothecene mycotoxins inhibit protein synthesis and activate inflammatory immune signaling?

Trichothecene mycotoxins, such as deoxynivalenol (DON), diacetoxyscirpenol (DAS), and verrucarin A, are potent eukaryotic translation inhibitors that severely disrupt cellular function and induce strong inflammatory responses.

Cellular and molecular mechanisms

• Ribosomal Inhibition: These toxins bind non-covalently to the peptidyl transferase center (PTC) at the A-site of the eukaryotic 60S ribosomal subunit (specifically targeting 28S rRNA). This physical blockage prevents aminoacyl-tRNA binding, halting translation elongation.
• Ribotoxic Stress Response: Translation arrest at the ribosome is sensed by the upstream kinase Hck, triggering a ribotoxic stress response. This rapidly phosphorylates and activates Mitogen-Activated Protein Kinase (MAPK) pathways—specifically p38, JNK, and ERK—and downstream transcription factors like NF-κB and AP-1.
• Inflammatory Cascades: NF-κB activation induces the production of pro-inflammatory cytokines (TNF-α, IL-6, and pro-IL-1β). Concurrently, secondary signals mediated by Src kinases and extracellular ATP promote ASC oligomerization and caspase-1 activation, assembling the NLRP3 inflammasome to drive pyroptosis and mature IL-1β secretion.

Comparative toxicity and potency

• Inhibitory Potency: While sharing a conserved mechanism, toxicity varies widely based on chemical structure. DON exhibits translation inhibition in the low-micromolar ($IC_{50}$) range. In contrast, DAS is approximately 90-fold more potent than DON, and verrucarin A exhibits nanomolar activity, making it 125- to 250-fold more active than DON.

Bottom line

• Bottom line: Trichothecene mycotoxins directly inhibit eukaryotic protein synthesis by binding the 60S ribosomal subunit, initiating a ribotoxic stress response that activates MAPK/NF-κB pathways and triggers the NLRP3 inflammasome to drive potent inflammatory immune signaling.