EDITORIAL published: 19 February 2020 doi: 10.3389/fimmu.2020.00236 Editorial: Role of Ribonucleases in Immune Response Regulation During Infection and Cancer Ester Boix 1*, Francesco Acquati 2 , Demetres Leonidas 3 and David Pulido 4 1 Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain, 2 Human Genetics Laboratory, Department of Biotechnology and Molecular Sciences, University of Insubria, Varese, Italy, 3 Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, Larissa, Greece, 4 The Jenner Institute, Medical Sciences Division, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom Keywords: RNaseA, RNaseT2, cancer, infection, innate immunity, oligomers Editorial on the Research Topic Role of Ribonucleases in Immune Response Regulation During Infection and Cancer Ribonucleases (RNases) are key players of the host immunity and contribute to maintaining tissue homeostasis and body fluid sterility. Secreted upon a diversity of cellular injuries, they mediate signaling processes, and have been classified as alarmins (1). Recent literature reveals how the immune response system uses common strategies to fight both cancer and infection. RNases participate in immune system adaptation to cellular stress conditions. They can shape the metabolism of cellular RNA, specifically target the non-coding RNA population, or even induce signal transduction in a catalytically independent manner (2–4). This Research Topic gathers some of the latest research on two secretory RNase families, RNaseA and RNaseT2, which participate in the host immune response and share similar mechanisms of action. The RNaseA family takes its name from bovine pancreatic RNaseA, one of the first and best enzymes characterized in the early 20th century (5, 6). It is vertebrate-specific and includes eight Edited and reviewed by: Linda F. Van Dyk, functional members in humans (7). In turn, the RNaseT2 family is broadly distributed across all University of Colorado Denver, kingdoms and has a unique member in humans (8). Nonetheless, we find huge similarities in United States their catalytic mechanisms and biological properties. Interestingly, both proteins have catalytically *Correspondence: dependent and independent immune-regulatory activities. In this issue, we include reviews and Ester Boix original research articles that focus on the immune defense role of the RNases in infection ester.boix@uab.es and cancer. Within the RNaseA family, we find several members with antimicrobial properties (2). Here, Specialty section: Boix et al. identified the human canonical members that mediate the eradication of macrophage This article was submitted to infection. Interestingly, the removal of intracellular dwelling bacteria is not dependent on the Viral Immunology, protein catalytic activity and is mediated by autophagy induction. The authors also observed a section of the journal how bacterial infection modulates the expression of endogenous RNases 3 and 6, suggesting Frontiers in Immunology a physiological role. In turn, the review by Spencer and co-workers highlights the enhanced Received: 18 December 2019 expression of both RNases in urinary tract infection. The RNases participate together with other Accepted: 29 January 2020 antimicrobial peptides in the bacterial clearance at the uroepithelial barrier. The authors propose Published: 19 February 2020 a task specialization whereby RNases 3 and 6 are released by activated infiltrating eosinophils and Citation: macrophages, respectively, and two additional RNases, RNases 4 and 7, are constitutively produced Boix E, Acquati F, Leonidas D and by epithelial cells to reinforce the kidney and bladder protection. In addition, RNase7 is abundantly Pulido D (2020) Editorial: Role of Ribonucleases in Immune Response released by keratinocytes and can protect the skin from pathogens. Harder et al. explore the Regulation During Infection and role of skin RNase7 during infection, with special attention to its immunomodulatory activities. Cancer. Front. Immunol. 11:236. The review includes the outlook of their very recent work, showing how RNase7 senses the host doi: 10.3389/fimmu.2020.00236 self-DNA as a skin damage signal and the subsequent activation of the cell antiviral response. Frontiers in Immunology | www.frontiersin.org 1 February 2020 | Volume 11 | Article 236 Boix et al. Editorial: RNases in Infection and Cancer On the other hand, secretory RNases are also protecting our the recently established role of T2 RNases in the regulation of tissues against other cell injuries, such as cell cycle dysregulation innate immunity seems to represent a key component of their in tumorigenesis. Indeed, RNases have long been known to tumor-suppressive activity. Indeed, in vivo studies focused on the be involved in the control of cancer growth (9). Several only human member of the T2 RNase family have consistently members of the RNaseA family have been reported to carry out shown that its tumor-suppressive activity is strictly dependent on oncosuppressive activity and have been proposed for antitumor the ability to recruit antitumor, M1-polarized host macrophages. therapy (10). Within this context, the review by Gotte and Moreover, the reported role of T2 RNases as wide-range stress Menegazzi explores the potential of RNaseA members to act response genes prompted the authors to include RNASET2 in as antitumor drugs. Secreted RNases can be cytotoxic when the growing family of alarmins, as molecules passively released entering the cell. Fortunately, the vertebrate cell cytosol has by necrotic cells or actively secreted by epithelial or immune a major protective shield against RNases, the proteinaceous cells to alert of dangerous events, such as the local occurrence ribonucleolytic inhibitor (RI). One way to evade RI is the of early-stage cancers. intrinsic ability of RNases to oligomerize and form homo- and Despite the extensive work applied to unraveling the even heterodimers. The activities of RNase natural and artificial mechanism of action of secretory RNases, little is known about oligomers are analyzed in light of the development of RNase- their physiological RNA substrates and how the released RNA based therapeutic applications. products regulate host immunity. Interestingly, recent reports Strikingly, RNases belonging to the T2 protein family have also reveal the key role of non-coding RNA fragments, such as recently been implicated in tumor suppression (8). Specifically, tRNA halves, that are generated upon the cleavage of specific the human RNASET2 gene has been consistently reported to act RNases and are associated with signaling pathways (15). Thereby, as a powerful, pleiotropic tumor suppressor (11). Of note, tumor secretory RNases will contribute to enlarge the ncRNA diversity suppression turned out to be an evolutionarily conserved feature and functionality (16). Mastering their cleavage selectivity and of T2 RNases (12) and to be carried out by means of both cell- immune-modulation properties should provide us the novel autonomous and non-autonomous mechanisms, among which tools for the specific removal of dysfunctional cells and the the establishment of cancer cell-tumor microenvironment cross- maintenance of healthy tissues. We are confident that a better talk was established to play a key role (13). In fact, recent understanding of the role of RNases would contribute to the studies have defined key cellular components of the innate development of new therapies against both cancer and infection. immune system, such as macrophages, as critical effectors of RNASET2-mediated tumor suppression in both in vitro and AUTHOR CONTRIBUTIONS in vivo experimental models (14). Within the frame of this Research Topic, the review by Acquati EB, FA, DL, and DP participated in the first manuscript draft. et al. summarizes the role played by members of the very ancient EB edited the final version and all authors revised it. All ribonuclease T2 gene family in innate immunity-mediated tumor authors listed have made a substantial, direct and intellectual suppression. The review provides an overview of recent data contribution to the work, and approved it for publication. demonstrating an evolutionarily conserved role for T2 RNases in the recruitment and/or activation of key innate immunity effector ACKNOWLEDGMENTS cells in several experimental models. Noteworthily, in keeping with the growing bulk of experimental evidence pointing at the We want to take the opportunity to thank all the authors and innate immune system as a key effector in cancer growth control, reviewers that have participated in this Research Topic. REFERENCES 6. Cuchillo CM, Nogués MV, Raines RT. Bovine pancreatic ribonuclease: fifty years of the first enzymatic reaction mechanism. Biochemistry. (2011) 1. Yang D, Chen Q, Rosenberg HF, Rybak SM, Newton DL, Wang ZY, 50:7835–41. doi: 10.1021/bi201075b et al. Human ribonuclease A superfamily members, eosinophil-derived 7. Cho S, Beintema JJ, Zhang J. 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