Ribonuclease/angiogenin inhibitor 1 regulates stress-induced subcellular localization of angiogenin and controls its growth and survival activities

Abstract

Angiogenin (ANG) promotes cell growth and survival. Under growth conditions, ANG undergoes nuclear translocation and is accumulated in nucleolus where it stimulates ribosomal RNA (rRNA) transcription. When cells are stressed, ANG mediates the production of tRNA-derived stress-induced small RNA (tiRNA) that reprograms protein translation into a survival mechanism. The ribonucleolytic activity of ANG is essential for both processes but how this activity is regulated is unknown. We report here that ribonuclease/angiogenin inhibitor1 (RNH1) controls both localization and activities of ANG. Under growth conditions, ANG is located in the nucleus and is not associated with RNH1 so that the ribonucleolytic activity is retained to ensure rRNA transcription, whereas cytoplasmic ANG is associated with and inhibited by RNH1 so that random cleavage of cellular RNA is prevented. Under stresses, ANG is located in cytoplasm and is concentrated in stress granules (SG) where it is not associated with RNH1 thus remains enzymatically active for tiRNA production. In contrast, nuclear ANG is associated with RNH1 in stressed cells to ensure that the enzymatic activity is inhibited and no unnecessary rRNA is produced to save anabolic energy. Knockdown of RNH1 abolished stress-induced relocalization of ANG and decreased cell growth and survival.