Human angiogenin is a potent cytotoxin in the absence of ribonuclease inhibitor
- 1Graduate Program in Cell and Molecular Biology, University of Wisconsin–Madison, Madison, Wisconsin 53706, USA
- 2Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin 53706, USA
- 3Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
- 4Department of Chemistry, University of Wisconsin–Madison, Madison, Wisconsin 53706, USA
- Corresponding author: rtraines{at}mit.edu
Abstract
Angiogenin (ANG) is a secretory ribonuclease that promotes the proliferation of endothelial cells, leading to angiogenesis. This function relies on its ribonucleolytic activity, which is low for simple RNA substrates. Upon entry into the cytosol, ANG is sequestered by the ribonuclease inhibitor protein (RNH1). We find that ANG is a potent cytotoxin for RNH1-knockout HeLa cells, belying its inefficiency as a nonspecific catalyst. The toxicity does, however, rely on the ribonucleolytic activity of ANG and a cytosolic localization, which lead to the accumulation of particular tRNA fragments (tRFs), such as tRF-5 Gly-GCC. These up-regulated tRFs are highly cytotoxic at physiological concentrations. Although ANG is well-known for its promotion of cell growth, our results reveal that ANG can also cause cell death.
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Article is online at http://www.rnajournal.org/cgi/doi/10.1261/rna.065516.117.
- Received January 3, 2018.
- Accepted May 8, 2018.
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