Functional roles of the human ribonuclease A superfamily in RNA metabolism and membrane receptor biology

Abstract

The human ribonuclease A (hRNase A) superfamily is comprised of 13 members of secretory RNases, most of which are recognized as catabolic enzymes for their ribonucleolytic activity to degrade ribonucleic acids (RNAs) in the extracellular space, where they play a role in innate host defense and physiological homeostasis. Interestingly, human RNases 9-13, which belong to a non-canonical subgroup of the hRNase A superfamily, are ribonucleolytic activity-deficient proteins with unclear biological functions. Moreover, accumulating evidence indicates that secretory RNases, such as human RNase 5, can be internalized into cells facilitated by membrane receptors like the epidermal growth factor receptor to regulate intracellular RNA species, in particular non-coding RNAs, and signaling pathways by either a ribonucleolytic activity-dependent or -independent manner. In this review, we summarize the classical role of hRNase A superfamily in the metabolism of extracellular and intracellular RNAs and update its non-classical function as a cognate ligand of membrane receptors. We further discuss the biological significance and translational potential of using secretory RNases as predictive biomarkers or therapeutic agents in certain human diseases and the pathological settings for future investigations.

Keywords: Angiogenin; Extracellular RNA; Receptor tyrosine kinase; Ribonuclease; Ribosomal RNA; Transfer RNA.

Figure 1.. A graphic summary of hRNase A superfamily in regulating RNA metabolism and membrane receptor biology.

Secretory hRNase1 and hRNase5/ANG are abundantly produced by endothelial cells. hRNase1 as an exRNA scavenger mainly contributes to blood vessel protection in some cardiovascular diseases. The clearance of excess exRNAs by hRNase1 administration has the potential to be a new regimen in clinical practice. Secretory hRNase5/ANG undergoes receptor-mediated endocytosis into cells by interacting with cell surface proteins, EGFR and plexin-B2. The internalized hRNase5/ANG plays a functional role in the metabolism of intracellular RNA in a ribonucleolytic activity-dependent or -independent manner. For instance, in response to cellular stress, cytoplasmic hRNase5/ANG participates in tRNA cleavage at positions close to the anticodon loop requiring ribonucleolytic activity and in turn mediates the production of 5′-tiRNA and 3′-tiRNA, leading to cell proliferation and survival. Moreover, hRNase5/ANG can be transported to the nucleolus, where it promotes rRNA transcription by binding to rDNA promoter in association with the formation of RNA Pol I pre-initiation complex. Nuclear hRNase5/ANG is also responsible for direct or indirect regulation mRNA transcription. The underlying mechanism is worthwhile to be further addressed, i.e., the involvement of the ribonucleolytic activity of hRNase5/ANG. Recently, a non-classical role of hRNase5/ANG in membrane receptor biology has been identified. Secretory hRNase5/ANG plays an oncogenic role as an EGFR ligand by binding to EGFR’s extracellular domain, activating EGFR (red stars) with tyrosine phosphorylation (p), and transmitting EGFR downstream signaling in the intracellular space. Notably, this EGFR ligand-like function of hRNase5/ANG occurs independent of its ribonucleolytic activity. Together, hRNase5/ANG-EGFR axis highlights a crosstalk of RNases between RNA metabolism and membrane receptor biology through cell surface receptor endocytosis and intracellular signal transduction. On the other hand, some RNases, such as hRNase2/EDN and hRNase3/ECP, are mainly involved in host defense against pathogens. Interestingly, among the host defense-related activities, some require the ribonucleolytic activity of RNases, such as the antiviral activity of hRNase2/EDN and hRNase3/ECP, whereas some do not, such as the antibacterial activity of hRNase3/ECP and hRNase7. Further details can be found in the main text. Not drawn to scale.

Figure 2.. The proposed model of elevated ANG as an EGFR ligand in the sensitization to erlotinib therapy in pancreatic cancer.

In brief, higher levels of ANG induce its binding to EGFR and activate EGFR signaling, which in turn promotes tumorigenesis and increases erlotinib sensitivity in PDAC patients [15]. (This research was originally published in Cancer Cell. Wang YN, Lee HH, Chou CK, Yang WH, Wei Y, Chen CT, Yao J, Hsu JL, Zhu C, Ying H, Ye Y, Wang WJ, Lim SO, Xia W, Ko HW, Liu X, Liu CG, Wu X, Wang H, Li D, Prakash LR, Katz MH, Kang Y, Kim M, Fleming JB, Fogelman D, Javle M, Maitra A, and Hung MC. Angiogenin/ribonuclease 5 is an EGFR ligand and a serum biomarker for erlotinib sensitivity in pancreatic cancer. Cancer Cell. 2018; 33(4):752–769.e8. DOI: https://doi.org/10.1016/j.ccell.2018.02.012 © 2018 Elsevier Inc.)