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 (HSPC). Here we show that TRAF6 overexpression in mouse HSPC resulted in impaired hematopoiesis and bone marrow failure. Through the use of 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 Cdc42 activation and accounted for hematopoietic defects in TRAF6-expressing HSPC. These results implicate Ub signaling in coordinating RNA processing by TLR pathways during an immune response and in premalignant hematologic diseases, such as MDS.

TIFAB Regulates USP15-Mediated p53 Signaling during Stressed and Malignant Hematopoiesis

“…Moreover, deletion of TIFAB in hematopoietic cells recapitulates features of human MDSs, including progressive cytopenias, altered myeloid differentiation, and propensity to develop bone marrow (BM) failure (Bennett et al, 1982;Starczynowski et al, 2010;Steensma, 2015Steensma, , 2018Tefferi and Vardiman, 2009;Weh et al, 1991). Increasing evidence indicates that aberrant innate immune signaling (Barreyro et al, 2018;Fang et al, 2017aFang et al, , 2017bRhyasen et al, 2013;Ribezzo et al, 2019), which we observe in TIFAB-deficient models, is sufficient to induce MDS phenotypes. Although TIFAB is within the deleted region in del(5q) MDSs and AML, it likely has pleotropic functions in hematopoietic cells, yet it remains a poorly characterized member of the TRAF-interacting protein family.…”

Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations

“…Multiple lines of evidence implicate innate immune signaling in MDS pathogenesis (Basiorka et al, 2016; Fang et al, 2014; Wei et al, 2013), including experiments demonstrating increased innate immune signaling contributes to MDS development in vivo (Fang et al, 2017; Varney et al, 2015). Increased activation of Toll-like receptor and IL-1 receptor signaling with downstream activation of MAPK and NF-κB pathways is widely reported in MDS, but the mechanistic basis for this activation have mostly been restricted to MDS with deletion of chromosome 5q (Fang et al, 2014, 2017; Starczynowski, 2014; Varney et al, 2015).…”

Therapeutic discovery for marrow failure with MDS predisposition using pluripotent stem cells

“…Deletion of SBDS in the bone marrow niche promotes genotoxic stress in hematopoietic cells through activation of inflammatory signaling in SDS mouse models (33). Increased levels of inflammatory cytokines activating the TLR and TGF-β pathways have been implicated in MDS pathogenesis (34)(35)(36).…”