Editors' ChoiceRNA Signals

RNases Signal Stress

See allHide authors and affiliations

Science Signaling  14 Apr 2009:
Vol. 2, Issue 66, pp. ec134
DOI: 10.1126/scisignal.266ec134

Two papers have identified a signaling function for RNase molecules in protecting cells from stress. Yamasaki et al. studied regulation of protein translation in the human U2OS osteosarcoma cell line. During stress, translation is inhibited through phosphorylation of eukaryotic translation initiation factor 2A (eIF2A). But Yamasaki et al. wanted to explain observations that some regulation of eIF2A is retained in cells expressing a mutant eIF2A missing the site of regulated phosphorylation. They found that cells exposed to oxidative stress or other stresses showed accumulation of RNA molecules derived from cleavage of tRNA. Angiogenin is a secreted ribonuclease that has been implicated in tumor formation through its effects to promote formation of blood vessels. Because angiogenin can selectively cleave tRNA, Yamasaki et al. used siRNA to deplete cells of angiogenin and found that such treatment inhibited stress-induced cleavage of tRNA. Similar depletion of RNH1 (ribonuclease or angiogenin inhibitor 1), an inhibitor of angiogenin, increased stress-induced production of the cleaved tRNA. Treatment of cells with recombinant angiogenin or transfection of them with tRNA fragments both inhibited protein synthesis. Thus, the authors conclude that cleavage of tRNA contributes to regulation of protein synthesis during stress and that stressed cells may signal to neighboring cells by secretion of angiogenin. Yeast cells also cleave tRNA when exposed to oxidative stress, and Thompson and Parker wanted to identify the RNase that accounted for this effect. Strains lacking the RNase Rny1p lost the tRNA cleavage response to oxidative stress. The authors tagged Rny1p with green fluorescent protein and showed that the labeled protein was released from the vacuole into the cytoplasm in response to oxidative stress. Overexpression of Rny1p caused apoptosis in yeast cells, and deletion of the RNY1 gene inhibited apoptosis in yeast mutants especially susceptible to apoptosis in response to stress. But Rny1p must do more than cleave tRNAs, because the effect of Rny1p to promote cell death was retained by mutants that lacked catalytic activity. Intriguingly, the human ortholog of Rny1p, RNASET2, has tumor-suppressing activity that is independent of its catalytic activity. Thus, Thompson and Parker suggest that release of Rny1 from the vacuole in response to stress (analogous in some ways to release of cytochrome c from mitochondria, which promotes apoptosis) has two effects: It causes cleavage of tRNA in the cytoplasm and presumably acts in some other way to influence signaling pathways controlling growth and cell death. In mammalian cells, the distinct RNase angiogenin appears to provide the former function, but the activity-independent effects may be related to the tumor-suppressive effects of Rny1’s ortholog, RNASET2.

D. M. Thompson, R. Parker, The RNase Rny1p cleaves tRNAs and promotes cell death during oxidative stress in Saccharomyces cerevisiae. J. Cell Biol. 185, 43–50 (2009). [Abstract] [Full Text]

S. Yamasaki, P. Ivanov, G.-f. Hu, P. Anderson, Angiogenin cleaves tRNA and promotes stress-induced translational repression. J. Cell Biol. 185, 35–42 (2009). [Abstract] [Full Text]