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Review
. 2019 Nov 5:10:2587.
doi: 10.3389/fimmu.2019.02587. eCollection 2019.

Innate Immune Response Regulation by the Human RNASET2 Tumor Suppressor Gene

Francesco Acquati  1 , Lorenzo Mortara  2 , Annarosaria De Vito  1 , Denisa Baci  2 , Adriana Albini  3   4 , Marco Cippitelli  5 , Roberto Taramelli  1 , Douglas M Noonan  2   4
Affiliations
Review

Innate Immune Response Regulation by the Human RNASET2 Tumor Suppressor Gene

Francesco Acquati et al. Front Immunol. .

Abstract

The link between cancer development or progression and immune system dysregulation has long been established. Virtually every cell type belonging to both the innate and adaptive immune system has been reported to be involved in a complex interplay that might culminate into either a pro- or anti-tumorigenic response. Among the cellular components of the innate immune system, cells belonging to the monocyte/macrophage lineage have been consistently shown to play a key role in the tumorigenic process. The most advanced human tumors are reported to be strongly infiltrated with Tumor-Associated Macrophages (TAMs) endowed with the ability to contribute to tumor growth and dissemination. However, given their widely acknowledged functional plasticity, macrophages can display anti-tumor properties as well. Based on these premises, experimental approaches to promote the in vivo macrophage shift from pro-tumor to anti-tumor phenotype represent one of the most promising research field aimed at developing immune system-mediated tumor suppressive therapies. In this context, the human RNASET2 oncosuppressor gene has emerged as a potential tool for macrophage-mediated tumor suppression. A growing body of experimental evidence has been reported to suggest a role for this gene in the regulation of macrophage activity in both in vitro and in vivo experimental models. Moreover, several recent reports suggest a role for this gene in a broad range of cell types involved in immune response, pointing at RNASET2 as a putative regulator of several functional features within the immune system.

Keywords: T2 RNases; innate immune response; stress response; targeting immunotherapy; tumor microenvironment; tumor suppression.

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Figures

Figure 1
Figure 1
Structural features and evolutionary conservation of T2 RNase proteins. (A) A Clustal Omega alignment of several members of the T2 RNase family, showing the wide evolutionary conservation of this enzymes. RNA cleavage by T2 RNases is mediated by histidine residues (red boxes) embedded into two highly conserved motifs dubbed CAS I and CAS II. The species included in the alignment are Saccharomices cerevisiae, Hirudo verbana, Danio rerio, Homo sapiens, Macaca mulatta, Rattus norvegicus, and Mus musculus. (B) Structure of human RNASET2. The RNASET2 primary sequence includes 256 aminoacid residues, with a predicted molecular weight of about 30 kDa. The core enzyme is colored in dark green in the figure. Among the protein's structural features, a 24-residues long signal peptide for secretion at the N-terminal (yellow bar) and the two canonical CAS sites (CAS I/II, red bars) responsible for the enzyme's catalytic activity (bearing a highly conserved key histidine residue at position 65 and 118, respectively) are shown in the figure. Three N-glycosylation sites (white horizontal lines), which increase the molecular weight of the native protein of about 6 kDa, are also shown (34). Finally, a putative TRAF-2 binding site (dark blue bar) was predicted in the C-terminal part of RNASET2 (light blue bar, starting form residue 214), which is less evolutionary conserved throughout evolution and has been suggested to be comprise a highly disordered loop (35). Within the cell, the RNASET2 protein is present in three forms of different sizes, namely 36, 31, and 27 kDa (34). The 36 kDa isoform represents the full-length and secreted form, which is easily detected in cell culture supernatants from RNASET2-expressing cells, whereas the other two isoforms represent intracellular protein isoforms originating from proteolytic cleavage of the full-length protein (B).
Figure 2
Figure 2
A model for human RNASET2-mediated tumor suppression. (A) In physiological contexts, most human cells express low or undetectable RNASET2 levels (https://www.ncbi.nlm.nih.gov/gene/8635), with the notable exception of spleen, lymph nodes and colon, three tissues highly involved in immune system function. This ubiquitous “baseline” RNASET2 expression can be related to the execution of intracellular or extracellular roles (some yet-to-be defined) possibly mediated by its catalytic activity. (B) When cells are locally exposed to a wide range of stresses, some of which are typically experienced by cancer cells (such as hypoxia, oxidative stress or nutritional starvation), they activate a “danger-response” program which involves, besides the activation of several endogenous stress response pathways, a massive increase in expression and secretion of RNASET2, which acts as an alarmin-like molecule to engage cells belonging to the innate immune system (mostly macrophages, but possibly other cellular components such as natural killer (NKs), dendritic cells (DCs) and granulocytes) to coordinate an immune-response-mediated tumor suppressive response. As previously described for several biological processes mediated by T2 RNases, the catalytic activity of the RNASET2 is not required to trigger this marked immune system-mediated response. Strikingly, the functional crosstalk between RNASET2 and cellular effectors of the innate immune system has been reported in several evolutionary distant species, suggesting an ancient key role of T2 RNases in immune-response mediated host defense.
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