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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Autoimmunity
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Cells, Cultured
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Hematopoiesis / genetics
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Hematopoietic Stem Cells / physiology*
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Heterogeneous Nuclear Ribonucleoprotein A1
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Heterogeneous-Nuclear Ribonucleoprotein Group A-B / genetics
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Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism*
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Immunity, Innate
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Myelodysplastic Syndromes / immunology*
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Precancerous Conditions / immunology*
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Signal Transduction* / genetics
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TNF Receptor-Associated Factor 6 / genetics
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TNF Receptor-Associated Factor 6 / metabolism*
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Toll-Like Receptors / metabolism
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Ubiquitination* / genetics
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cdc42 GTP-Binding Protein / metabolism
Substances
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Cdc42 protein, mouse
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Heterogeneous Nuclear Ribonucleoprotein A1
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Heterogeneous-Nuclear Ribonucleoprotein Group A-B
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Hnrnpa1 protein, mouse
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TNF Receptor-Associated Factor 6
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Toll-Like Receptors
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cdc42 GTP-Binding Protein