Gomez-Diaz Carlos, Greulich Wilhelm, Wefers Benedikt, Wang Meiyue, Bolsega Silvia, Effern Maike, Varga Daniel P, Han Zhe, Chen Minyi, Bérouti Marleen, Leonardi Natascia, Schillinger Ulrike, Holzmann Bernhard, Liesz Arthur, Roers Axel, Hölzel Michael, Basic Marijana, Wurst Wolfgang, Hornung Veit
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
Institute of Developmental Genetics, Helmholtz Zentrum München , Neuherberg, Germany.
J Exp Med. 2025 Mar 3;222(3). doi: 10.1084/jem.20241424. Epub 2025 Jan 24.
RNA-sensing TLRs are strategically positioned in the endolysosome to detect incoming nonself RNA. RNase T2 plays a critical role in processing long, structured RNA into short oligoribonucleotides that engage TLR7 or TLR8. In addition to its positive regulatory role, RNase T2 also restricts RNA recognition through unknown mechanisms, as patients deficient in RNase T2 suffer from neuroinflammation. Consistent with this, mice lacking RNase T2 exhibit interferon-dependent neuroinflammation, impaired hematopoiesis, and splenomegaly. However, the mechanism by which RNase T2 deficiency unleashes inflammation in vivo remains unknown. Here, we report that the inflammatory phenotype found in Rnaset2-/- mice is completely reversed in the absence of TLR13, suggesting aberrant accumulation of an RNA ligand for this receptor. Interestingly, this TLR13-driven inflammatory phenotype is also fully present in germ-free mice, suggesting a role for RNase T2 in limiting erroneous TLR13 activation by an as yet unidentified endogenous ligand. These results establish TLR13 as a potential self-sensor that is kept in check by RNase T2.
RNA 传感 Toll 样受体（TLRs）策略性地定位于内溶酶体中，以检测进入的非自身 RNA。核糖核酸酶 T2 在将长链结构化 RNA 加工成与 TLR7 或 TLR8 结合的短寡核糖核苷酸过程中起关键作用。除了其正向调节作用外，核糖核酸酶 T2 还通过未知机制限制 RNA 识别，因为核糖核酸酶 T2 缺陷患者会出现神经炎症。与此一致的是，缺乏核糖核酸酶 T2 的小鼠表现出干扰素依赖性神经炎症、造血功能受损和脾肿大。然而，核糖核酸酶 T2 缺乏在体内引发炎症的机制仍然未知。在此，我们报告在 Rnaset2-/- 小鼠中发现的炎症表型在没有 TLR13 的情况下完全逆转，这表明该受体的 RNA 配体异常积累。有趣的是，这种由 TLR13 驱动的炎症表型在无菌小鼠中也完全存在，这表明核糖核酸酶 T2 在限制尚未鉴定的内源性配体对 TLR13 的错误激活中发挥作用。这些结果确立了 TLR13 作为一种潜在的自身传感器，受核糖核酸酶 T2 的抑制。
