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.

Selective cleavage of ncRNA and antiviral activity by human RNase2/EDN in a macrophage infection model

“…For example, Onconase selectivity for specific tRNAs was attributed to the presence in vivo of RNA binding proteins that might protect RNA regions from RNase activity [52,61]. In this context, we should consider the formation of regulatory complexes, such as the RISC formation, the binding of Argonaute (AGO) subunits [62] or interactions with the RNHI. On its turn, the released tRNA products would regulate the formation of cellular complexes.…”

“…On the other hand, we should also take into account the protein traffic and accessibility to the distinct subcellular compartments in the assayed experimental conditions. For example, in contrast to RNase5, mostly located at the nucleus, RNase2 is associated to the endolysosomal compartment [47,48,62]. In addition, cleavage of cellular mature tRNAs might occur during stress conditions, when leakage of the RNases to the cytosol is favoured.…”

“…Accessibility of tRNAs will also depend on their potential entrapment in Tbox riboswitch or RNA granules, which are abundant in starvation situation and have an unequal propensity to protect tRNA from cleavage. Besides, proteomic analysis revealed the presence of RNHI within stress granules [73], an inhibitor protein that can complex to RNase5/Ang and other regulatory proteins to control cell translation [62].…”

Recognized and Potentially New Biomarkers—Their Role in Diagnosis and Prognosis of Cardiovascular Disease

“…Given the established roles of ANG in the etiology of disorders such as cancer, infection, and rare diseases, such as amyotrophic lateral sclerosis, further investigations of the molecular mechanisms mediated by ANG are required [ 150 ]. One should also pay attention to the ANG—ribonuclease inhibitor (RNH1) system, which is seen as one of the auxiliary parts of the translation machinery, where RNH1 is regarded as a “sentinel” to protect the RNA from extracellular RNAses [ 151 ].…”

Possible Roles of tRNA Fragments, as New Regulatory ncRNAs, in the Pathogenesis of Rheumatoid Arthritis

“…SLFN2 binds to tRNAs and protects them from cleavage by ANG [101]. The production of tiRNA is basically regulated by ANG and RNH1 [102,103]. However, at least in T cells, SLFN2 is a new molecule that regulates the production of tiRNA, together with ANG and RNH1 (Figure 2).…”