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Role of Ribonucleases in Immune Response Regulation during Infection and Cancer

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Ribonucleases (RNases) participate in a diversity of biological processes from the removal of RNA debris to the specific processing of the human transcriptome. Recent advances have expanded the roles ascribed to several families of RNases as critical immune response regulators during stress conditions such as ...

Ribonucleases (RNases) participate in a diversity of biological processes from the removal of RNA debris to the specific processing of the human transcriptome. Recent advances have expanded the roles ascribed to several families of RNases as critical immune response regulators during stress conditions such as infection, tissue injury, and cancer.

In this regard, recent studies have highlighted the key immunomodulatory and antimicrobial roles of RNases ranging from homeostasis to maintenance of body fluid sterility. During stress conditions, such as tissue infection and inflammation, the expression and secretion of these RNases not only facilitates the clearance of cellular RNA debris from damaged cells but they also act as key signalling molecules regulating tissue remodelling and repair. For instance, the RNaseA superfamily, which is a vertebrate-specific family that comprises eight functional members, is secreted by blood and epithelial cells during infection and inflammation. One of the most intriguing RNaseA family members is RNase5, also called Angiogenin, which is secreted in response to cellular stress and specific T cell activation following viral infection. Another emerging endoribonuclease mediating the antimicrobial and immune response is the interferon (IFN)-regulated RNaseL, which dimerizes upon binding to 2′-5′-linked oligoadenylate (2-5A) and promotes both cellular and viral ssRNA cleavage. This generates small RNAs capable of inducing the activation of acid-inducible gene-I (RIG-I)-like receptors or the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome. Moreover, RNaseL modulates the cytoskeleton through the interaction with several actin-binding proteins like filamin A, thus contributing to maintaining the cellular barrier during viral infection.

In addition to their role in infection, RNases have also been implicated in cancer. For instance, RNase5 participates in almost every step of tumorigenesis, promoting tumour cell survival, proliferation, adhesion, migration and invasion. The RNaseT2 family, which is another group of secreted enzymes that works as immune-signalling molecules, is conserved from bacteria to vertebrates. Recent experimental data suggest that the human RNaseT2 should be classified as an “alarmin”, whose role as a stress response effector is at the crossroad between cancer and innate immunity. Indeed, RNASET2 expression and secretion is known to be significantly increased following exposure of human cancer cells to a wide range of stress conditions such as hypoxia or oxidative stress. Moreover, xenograft-based assays have demonstrated that human RNASET2 has tumor suppressive activity in vivo, which is dependent on the recruitment of M1 host macrophages. Moreover, recombinant RNASET2 protein was recently found to act as a chemokine for human macrophages in vitro. The contribution of RNaseT2 in innate immune response has been reported in both vertebrate and invertebrate model systems, indicating its ancient role in stress-mediated immunoregulation.

This Research Topic aims to provide an overall perspective on the current knowledge of RNases with immunomodulatory properties and their role in health and disease. We encourage the submission of Reviews, Methods and Original Research articles covering the biophysical, biochemical and physiological aspects of RNases involved in regulation of immune response to infection and cancer. We welcome articles covering, but not limited to, the following topics:

1. Role of RNases in Infection:
(a) Role of RNases in innate immune response to microbial infection
(b) Role of RNases in innate immune response to viral infection
(c) Role of RNases in antimicrobial response against infection

2. Role of RNases in Cancer:
(a) Role of RNases in modulating the immune system in cancer
(b) Role of RNases in tumorigenesis
(c) Targeting RNases for the immunotherapy of cancer


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