RNASET2 is required for ROS propagation during oxidative stress-mediated cell death

Abstract

RNASET2 is a ubiquitously expressed acidic ribonuclease that has been implicated in diverse pathophysiological processes including tumorigeneis, vitiligo, asthenozoospermia, and neurodegeneration. Prior studies indicate that RNASET2 is induced in response to oxidative stress and that overexpression of RNASET2 sensitizes cells to reactive oxygen species (ROS)-induced cell death through a mechanism that is independent of catalytic activity. Herein, we report a loss-of-function genetic screen that identified RNASET2 as an essential gene for lipotoxic cell death. Haploinsufficiency of RNASET2 confers increased antioxidant capacity and generalized resistance to oxidative stress-mediated cell death in cultured cells. This function is critically dependent on catalytic activity. Furthermore, knockdown of RNASET2 in the Drosophila fat body confers increased survival in the setting of oxidative stress inducers. Together, these findings demonstrate that RNASET2 regulates antioxidant tone and is required for physiological ROS responses.

A genome-wide polygenic approach to HIV acquisition uncovers link to inflammatory bowel disease and identifies potential novel genetic variants

“…rs9459882 is an intronic variant within CCR6 , a chemokine receptor involved in the migration of T cells 38 . rs1819333 maps to the 5’UTR region of the Ribonuclease T2 gene (RNASET2) , which is involved in RNA binding 39 and ROS propagation 40 . These SNPs are eQTLs for RNASET2 and CCR6 in blood 37 .…”

Overexpression of Murine Rnaset2 in a Colon Syngeneic Mouse Carcinoma Model Leads to Rebalance of Intra-Tumor M1/M2 Macrophage Ratio, Activation of T Cells, Delayed Tumor Growth, and Rejection

“…In fact, human RNASET2 overexpression in two independent human ovarian cancer cell lines, followed by challenging of immunodeficient mouse models with these cells, showed a marked tumor suppressive effect coupled with a RNASET2-mediated recruitment of M1-polarized host macrophages within the tumor mass [1,2]. These data, coupled to the well-established notion of T2 RNases as stress response genes [8,9], strongly suggest that human RNASET2 secretion by cancer cells might represent a "danger" signal for cells belonging to the monocyte/macrophage lineage, whose role would be to trigger an effective host immune response. Of note, the macrophage-activating role of T2 RNases has been recently confirmed in species far away from mammals in term of evolutionary distance, such as the invertebrate Hirudo verbana [10], thus pointing at T2 RNases as highly conserved immune system-related stress response proteins acting across many Phyla.The concept that the immune system can recognize and control tumor growth was mainly based on the many in vivo data related to immunoediting phenomenon in preclinical models and humans [11,12], as well as in in vitro studies [13].…”

Consensus report of the 8 and 9th Weinman Symposia on Gene x Environment Interaction in carcinogenesis: novel opportunities for precision medicine

“…Once they reach the mesothelium, asbestos fibres cause mesothelial cell death and chronic inflammation, associated with the release of damageassociated molecular patterns (DAMPs) molecules and cytokines [27]. Among these DAMPs, the active and passive release of different isoforms of high-mobility group box 1 (HMGB1) protein [31] sustains the chronic inflammatory response, with secretion of TNF-α and reactive oxygen species (ROS) [32,33] (Fig. 4).…”