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

Nature immunology | 2017

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.

Pubmed ID: 28024152 RIS Download

Associated grants

  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK102759
  • Agency: NHLBI NIH HHS, United States
    Id: R35 HL135787
  • Agency: NHLBI NIH HHS, United States
    Id: R01 HL114582
  • Agency: NCI NIH HHS, United States
    Id: T32 CA117846
  • Agency: NCRR NIH HHS, United States
    Id: S10 RR027015
  • Agency: NHLBI NIH HHS, United States
    Id: R01 HL111103
  • Agency: NIDDK NIH HHS, United States
    Id: P30 DK090971

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