Angiogenin (ANG)-Ribonuclease Inhibitor (RNH1) System in Protein Synthesis and Disease

Abstract

Protein synthesis is a highly complex process executed by well-organized translation machinery. Ribosomes, tRNAs and mRNAs are the principal components of this machinery whereas RNA binding proteins and ribosome interacting partners act as accessory factors. Angiogenin (ANG)-Ribonuclease inhibitor (RNH1) system is one such accessory part of the translation machinery that came into focus afresh due to its unconventional role in the translation. ANG is conventionally known for its ability to induce blood vessel formation and RNH1 as a "sentry" to protect RNAs from extracellular RNases. However, recent studies suggest them to be important in translation regulation. During cell homeostasis, ANG in the nucleus promotes rRNA transcription. While under stress, ANG translocates to the cytosol and cleaves tRNA into fragments which inhibit ribosome biogenesis and protein synthesis. RNH1, which intimately interacts with ANG to inhibit its ribonucleolytic activity, can also bind to the 40S ribosomes and control translation by yet to be known mechanisms. Here, we review recent advancement in the knowledge of translation regulation by the ANG-RNH1 system. We also gather information about this system in cell homeostasis as well as in pathological conditions such as cancer and ribosomopathies. Additionally, we discuss the future research directions and therapeutic potential of this system.

Keywords: Angiogenin (ANG); RNases; Ribonuclease inhibitor (RNH1); mRNA translation regulation; ribosomal heterogeneity; transcript-specific translation and ribosomopathies.

Figure 1

Mechanisms of ANG-RNH1 mediated translational regulation: (A) ANG regulates rRNA synthesis in nucleolus—ANG cleaves pRNAs in the nucleolus to de-repress the rDNA transcription, activates rRNA production and subsequently enhance global protein synthesis by increased ribosome biogenesis. (B) ANG cleave tRNAs in cytoplasm—ANG in response to various stresses cleave tRNAs in cytoplasm to produce tiRNAs, which ultimately inhibits translation initiation. (C) RNH1 regulates mRNA specific translation—RNH1 binds to 40S ribosomal subunits to possibly initiate translation on specific mRNAs (D) RNH1 controls miR-21 biogenesis in nucleus—RNH1 in the nucleus interacts with pri-miR-21 and the Drosha complex to enhance processing into mature miR-21. (E) RNH1 bind miRNAs and controls target repression—Cytoplasmic RNH1 interacts with miRNA machinery and recruits miR-99a, miR-99b, and miR-101 on 3′UTR of mTOR mRNA for its repression. (F) RNH1 binds polysomes and possibly stabilize them—RNH1 is present in polysome fractions and it might maintain the integrity of the polysomes possibly by scavenging RNases. (G) RNH1 and ANG present in stress granules—RNH1 and ANG are components of stress granules with unknown function. Mechanisms highlighted with red boxes are under explored and need further detailed mechanistic investigation. All schematics are representative and not to the scale.