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

Autor: Fang J; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Bolanos LC; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Choi K; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Liu X; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Christie S; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Akunuru S; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Kumar R; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Wang D; Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Chen X; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Greis KD; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Stoilov P; Department of Biochemistry, West Virginia University, Morgantown, West Virginia, USA., Filippi MD; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Maciejewski JP; Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA., Garcia-Manero G; Department of Leukemia, Maryland Anderson Cancer Center, Houston, Texas., Weirauch MT; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.; Division of Biomedical Informatics, Cincinnati Children's Hospital Research Medical Center, Cincinnati, Ohio, USA.; Division of Developmental Biology, Cincinnati Children's Hospital Research Medical Center, Cincinnati, Ohio, USA., Salomonis N; Division of Biomedical Informatics, Cincinnati Children's Hospital Research Medical Center, Cincinnati, Ohio, USA., Geiger H; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Zheng Y; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Starczynowski DT; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Jazyk: angličtina
Zdroj: Nature immunology [Nat Immunol] 2017 Feb; Vol. 18 (2), pp. 236-245. Date of Electronic Publication: 2016 Dec 26.
DOI: 10.1038/ni.3654
Abstrakt: 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.
Databáze: MEDLINE
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