Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia.
Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia.
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DOI：
10.1038/ni.3654
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发表时间：
2017-02
影响因子：
30.5
通讯作者：
Starczynowski DT
中科院分区：
文献类型：
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作者：
Fang J;Bolanos LC;Choi K;Liu X;Christie S;Akunuru S;Kumar R;Wang D;Chen X;Greis KD;Stoilov P;Filippi MD;Maciejewski JP;Garcia-Manero G;Weirauch MT;Salomonis N;Geiger H;Zheng Y;Starczynowski DT
Toll样受体（TLR）活化有助于恶性前血液学病症，例如骨髓增生异常综合征（MDS）。TRAF 6是一种具有泛素（Ub）连接酶活性的TLR效应子，在MDS造血干/祖细胞（HSPC）中过表达。在这里，我们表明TRAF 6在小鼠HSPC中的过表达导致造血功能受损和骨髓衰竭。通过使用全局Ub筛选，我们确定了hnRNPA 1，一种RNA结合蛋白和辅助剪接因子，作为TRAF 6的底物。hnRNPA 1的TRAF 6泛素化调节Arhgap 1的选择性剪接，这导致Cdc 42活化并解释了表达TRAF 6的HSPC中的造血缺陷。这些结果暗示Ub信号在免疫应答过程中和恶性血液病（如MDS）中通过TLR途径协调RNA加工。
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 (HSPC). Here we show that TRAF6 overexpression in mouse HSPC resulted in impaired hematopoiesis and bone marrow failure. Through the use of 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 Cdc42 activation and accounted for hematopoietic defects in TRAF6-expressing HSPC. These results implicate Ub signaling in coordinating RNA processing by TLR pathways during an immune response and in premalignant hematologic diseases, such as MDS.