title: Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia.
abstract: 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.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Lyndsey C
authors.initials: LC
authors.lastname: Bolanos
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Kwangmin
authors.initials: K
authors.lastname: Choi
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Xiaona
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Susanne
authors.initials: S
authors.lastname: Christie
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Shailaja
authors.initials: S
authors.lastname: Akunuru
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Rupali
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Dehua
authors.initials: D
authors.lastname: Wang
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Greis
authors.affiliation: Department of Biochemistry, West Virginia University, Morgantown, West Virginia, USA.
authors.forename: Peter
authors.identifier: 0000-0003-1108-7271
authors.initials: P
authors.lastname: Stoilov
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Marie-Dominique
authors.initials: MD
authors.lastname: Filippi
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.affiliation: Department of Leukemia, Maryland Anderson Cancer Center, Houston, Texas.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.affiliation: 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.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Weirauch
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Research Medical Center, Cincinnati, Ohio, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Salomonis
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Geiger
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Starczynowski
mesh_terms: D000818:Animals; D015551:Autoimmunity; D002478:Cells, Cultured; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009190:Myelodysplastic Syndromes / Q000276:immunology*; D011230:Precancerous Conditions / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: C581598:Cdc42 protein, mouse; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C000619657:Hnrnpa1 protein, mouse; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D020764:cdc42 GTP-Binding Protein