1st International Meeting on RNA and RNases

The RNASET2 protein encodes the only human member of the highly conserved T2/Rh/S family of extracellular ribonucleases. RNASET2 has long been shown to display both oncosuppressive and immunoregulatory functions across various cancer types, possibly acting as an alarmin molecule providing a Danger-Associated Molecular Pattern (DAMP) signal in the tumor microenvironment, which in turn engages cells with anti-tumoral activity from the innate immune system. Such non cell-autonomous role of RNASET2 was found to be coupled with a marked cell-autonomous oncosuppressive function affecting several cancer-related parameters. Here, both features have been investigated and confirmed in a cellular model of one of the most common cancer types (i.e. prostate cancer), focusing on a wide panel of in vitro and in vivo assay. These data further suggest that RNASET2-mediated tumor suppression is driven by a functional cross-talk between cancer cells-derived RNASET2 and cellular components of the innate immune system, in particular cells from monocyte/macrophage lineage. Furthermore, mutations in the human RNASET2 gene have been recently reported in several independent patients affected by Aicardi-Goutières Syndrome (AGS), a rare Mendelian brain leukoencephalopathy. AGS has been linked to loss-of-function mutations in several genes involved in nucleic acid sensing, signaling or processing and presents a characteristic “interferon signature”, represented by increased levels of interferon-alpha (IFN-a) and IFN-a-regulated genes in patients’ cerebrospinal fluid and peripheral blood. These observations collectively define AGS as a brain inflammatory disease triggered by induction of an excessive type-I interferon-mediated innate immune response, possibly driven by the accumulation of endogenous nucleic acids. Here, we analyzed independent mutant RNASET2 alleles carried by AGS patients and found them to encode a functionally defective protein, whose catalytic activity, intracellular distribution and secretion pattern are significantly impaired compared to the wild-type allele-encoded protein. Expression of the mutant alleles in the RNASET2-null MCF7 cancer cell line was also found to be associated with the AGS-associated inferferon signature. Finally, we found preliminary evidence suggesting a role for the Unfolded Protein Response (UPR) within the endoplasmic reticulum as possible pathogenetic mechanism for RNASET2-mediated AGS. We thus propose human RNASET2 as novel member of the increasing family of nucleic acid sensing/signalling genes involved in the pathogenesis of AGS. Thus, despite the clear difference in the pathogenetic mechanisms underlying cancer and AGS, the role played by human RNASET2 in both pathologies suggest a common link, which likely resides on the role played by this protein in the regulation of key functions in the innate immune system compartment.