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Ubiquitination of the spliceosome auxiliary factor hnRNPA1 by TRAF6 links chronic innate immune signaling with hematopoietic defects and myelodysplasia

ABSTRACT: Toll-like receptors (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.

ORGANISM(S): Mus musculus

PROVIDER: GSE64542 | GEO | 2016/12/20

SECONDARY ACCESSION(S): PRJNA271282

REPOSITORIES: GEO

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