Fang Jing, Bolanos Lyndsey C, Choi Kwangmin, Liu Xiaona, Christie Susanne, Akunuru Shailaja, Kumar Rupali, Wang Dehua, Chen Xiaoting, Greis Kenneth D, Stoilov Peter, Filippi Marie-Dominique, Maciejewski Jaroslaw P, Garcia-Manero Guillermo, Weirauch Matthew T, Salomonis Nathan, Geiger Hartmut, Zheng Yi, Starczynowski Daniel T
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Nat Immunol. 2017 Feb;18(2):236-245. doi: 10.1038/ni.3654. Epub 2016 Dec 26.
Toll-like receptor (TLR) activation contributes to premalignant hematologic conditions, such as myelodysplastic syndromes (MDS). TRAF6, a TLR effector with ubiquitin (Ub) ligase activity, is overexpressed in MDS hematopoietic stem/progenitor cells (HSPCs). We found that TRAF6 overexpression in mouse HSPC results in impaired hematopoiesis and bone marrow failure. Using a global Ub screen, we identified hnRNPA1, an RNA-binding protein and auxiliary splicing factor, as a substrate of TRAF6. TRAF6 ubiquitination of hnRNPA1 regulated alternative splicing of Arhgap1, which resulted in activation of the GTP-binding Rho family protein Cdc42 and accounted for hematopoietic defects in TRAF6-expressing HSPCs. These results implicate Ub signaling in coordinating RNA processing by TLR pathways during an immune response and in premalignant hematologic diseases, such as MDS.
Toll样受体（TLR）激活促成了癌前血液学病症，如骨髓增生异常综合征（MDS）。TRAF6是一种具有泛素（Ub）连接酶活性的TLR效应器，在MDS造血干/祖细胞（HSPC）中过表达。我们发现，小鼠HSPC中TRAF6的过表达导致造血功能受损和骨髓衰竭。通过全基因组泛素筛选，我们鉴定出hnRNPA1，一种RNA结合蛋白和辅助剪接因子，作为TRAF6的底物。TRAF6对hnRNPA1的泛素化调节了Arhgap1的可变剪接，这导致GTP结合Rho家族蛋白Cdc42的激活，并解释了表达TRAF6的HSPC中的造血缺陷。这些结果表明泛素信号在免疫反应期间通过TLR途径协调RNA加工以及在癌前血液学疾病（如MDS）中发挥作用。
