Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia

被引：84

作者：

Fang, Jing ^{[1
,11
]}

Bolanos, Lyndsey C. ^{[1
]}

Choi, Kwangmin ^{[1
]}

Liu, Xiaona ^{[1
]}

Christie, Susanne ^{[1
]}

Akunuru, Shailaja ^{[1
]}

Kumar, Rupali ^{[1
]}

Wang, Dehua ^{[2
,3
]}

Chen, Xiaoting ^{[4
]}

Greis, Kenneth D. ^{[5
]}

Stoilov, Peter ^{[6
]}

Filippi, Marie-Dominique ^{[1
]}

Maciejewski, Jaroslaw P. ^{[7
]}

Garcia-Manero, Guillermo ^{[8
]}

Weirauch, Matthew T. ^{[4
,9
,10
]}

Salamonis, Nathan ^{[9
]}

Geiger, Hartmut ^{[1
]}

Zheng, Yi ^{[1
]}

Starczynowski, Daniel T. ^{[1
,5
]}

机构：

[1] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA

[2] Cincinnati Childrens Hosp Med Ctr, Div Pathol, Cincinnati, OH 45229 USA

[3] Cincinnati Childrens Hosp Med Ctr, Lab Med, Cincinnati, OH 45229 USA

[4] Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol, Cincinnati, OH 45229 USA

[5] Cincinnati Childrens Hosp Med Ctr, Dept Canc Biol, Cincinnati, OH 45229 USA

[6] West Virginia Univ, Dept Biochem, Morgantown, WV 26506 USA

[7] Cleveland Clin, Dept Translat Hematol & Oncol Res, Taussig Canc Inst, Cleveland, OH 44106 USA

[8] Maryland Anderson Canc Ctr, Dept Leukemia, Houston, TX USA

[9] Cincinnati Childrens Hosp Res Med Ctr, Div Biomed Informat, Cincinnati, OH USA

[10] Cincinnati Childrens Hosp Res Med Ctr, Div Dev Biol, Cincinnati, OH USA

[11] Univ South Carolina, South Carolina Coll Pharm, Dept Drug Discovery & Biomed Sci, Columbia, SC 29208 USA

来源：

NATURE IMMUNOLOGY | 2017年 / 18卷 / 02期

关键词：

HEMATOPOIETIC STEM-CELLS; PROGENITOR CELLS; CDC42; GTPASE; IN-VIVO; EXPRESSION; PROTEINS; REVEALS; GENE; A1; RECOGNITION;

D O I：

10.1038/ni.3654

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.h

引用

页码：236 / 245

页数：10

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