Skewed endosomal RNA responses from TLR7 to TLR3 in RNase T2-deficient macrophages
Skewed endosomal RNA responses from TLR7 to TLR3 in RNase T2-deficient macrophages
复制标题
DOI：
10.1093/intimm/dxab033
复制
发表时间：
2021-06-23
影响因子：
4.4
通讯作者：
Miyake, Kensuke
中科院分区：
文献类型：
--
作者：
Liu, Kaiwen;Sato, Ryota;Miyake, Kensuke
核糖核酸酶T2是一种广泛表达的核糖核酸酶，它在内体区室中降解RNA。RNA受体，即双链RNA（dsRNA）感应型Toll样受体3（TLR3）和单链RNA（ssRNA）感应型TLR7，定位于小鼠巨噬细胞的内体区室。我们在此研究了核糖核酸酶T2在巨噬细胞中对TLR3和TLR7反应的作用。巨噬细胞表达核糖核酸酶T2以及核糖核酸酶A家族成员核糖核酸酶4。核糖核酸酶T2也在浆细胞样树突状细胞和常规树突状细胞中表达。用双链RNA或I型干扰素（IFN）处理会上调核糖核酸酶T2的表达，但不会上调核糖核酸酶4的表达。巨噬细胞中核糖核酸酶T2的缺失会上调TLR3反应，但会削弱TLR7反应。从机制上讲，核糖核酸酶T2在体外可降解双链RNA和单链RNA，其突变体在RNA降解与纠正改变的TLR3和TLR7反应之间呈现正相关。H122A和C188R核糖核酸酶T2突变，而非H69A和E118V突变，会削弱RNA降解以及纠正改变的TLR3和TLR7反应。骨髓来源巨噬细胞中的核糖核酸酶T2从早期内体到溶酶体广泛分布，并与内化的TLR3配体聚肌胞苷酸（poly(I:C)）共定位。这些结果表明，内体/溶酶体中依赖核糖核酸酶T2的RNA降解分别对巨噬细胞中的TLR3和TLR7反应起负向和正向调节作用。
RNase T2, a ubiquitously expressed RNase, degrades RNAs in the endosomal compartments. RNA sensors, double-stranded RNA (dsRNA)-sensing Toll-like receptor 3 (TLR3) and single-stranded RNA (ssRNA)-sensing TLR7, are localized in the endosomal compartment in mouse macrophages. We here studied the role of RNase T2 in TLR3 and TLR7 responses in macrophages. Macrophages expressed RNase T2 and a member of the RNase A family RNase 4. RNase T2 was also expressed in plasmacytoid and conventional dendritic cells. Treatment with dsRNAs or type I interferon (IFN) up-regulated expression of RNase T2 but not RNase 4. RNase T2-deficiency in macrophages up-regulated TLR3 responses but impaired TLR7 responses. Mechanistically, RNase T2 degraded both dsRNAs and ssRNAs in vitro, and its mutants showed a positive correlation between RNA degradation and the rescue of altered TLR3 and TLR7 responses. H122A and C188R RNase T2 mutations, not H69A and E118V mutations, impaired both RNA degradation and the rescue of altered TLR3 and TLR7 responses. RNase T2 in bone marrow-derived macrophages was broadly distributed from early endosomes to lysosomes, and colocalized with the internalized TLR3 ligand poly(I:C). These results suggest that RNase T2-dependent RNA degradation in endosomes/lysosomes negatively and positively regulates TLR3 and TLR7 responses, respectively, in macrophages.