We have previously hypothesized that rRNA cleavage might yield a double-stranded (ds) hairpin fragments capable of activating ribosome-associated PKR through its dsRNAbinding sites (Li and Pestka, 2008) . The data presented here do not support this hypothesis. First, PKR and Hck are activated by DON within minutes (Zhou et al., 2003b (Zhou et al., , 2005b , whereas DON-induced rRNA cleavage was detectable only after 2 h and required relatively higher DON concentrations. Second, suppression of DON-induced rRNA cleavage by PKR, Hck, and p38 inhibitors suggests that their activation is an upstream rather than downstream event. We therefore propose an alternative hypothesis in which entry of DON into the cell rapidly disrupts the conformation of rRNA yielding accessible intact hairpin loops at the surface of ribosome that would be capable of activating PKR or other double-stranded RNAbinding proteins. These events would initiate a stress response that would, especially at high toxin concentrations, ultimately drive rRNA cleavage in concert with apoptosis. This hypothesis is highly consistent with the growing recognition that damage-associated molecular patterns (DAMPs) initiate noninfectious innate immune and inflammatory responses (Newton and Dixit, 2012) . Bulavin et al. (1999) have previously shown that p38 mediates p53 phosphorylation. It was thus notable that rRNA cleavage was found here to be inhibited by pifithrin-a, a compound that reversibly inhibits both p53-dependent transactivation of p53-responsive genes and apoptosis, as well as by pifithrin-l, which blocks p53 interaction with Bcl-2 family proteins and selectively inhibits p53 translocation to mitochondria. Relatedly, we have previously demonstrated that DON induces translocation of BAX (a member of Bcl-2 family) to mitochondria and release of cytochrome c leading to apoptosis (Zhou et al., 2005a) . Finally, DON-induced rRNA cleavage was completely suppressed by the pan caspase inhibitor Z-VAD-FMK, indicating that activation of caspases was a prerequisite of rRNA cleavage.