TRAF6 Mediates Basal Activation of NF-κB Necessary for Hematopoietic Stem Cell Homeostasis

Abstract

SUMMARYBasal nuclear factor κB (NF-κB) activation is required for hematopoietic stem cell (HSC) homeostasis in the absence of inflammation; however, the upstream mediators of basal NF-κB signaling are less well understood. Here, we describe TRAF6 as an essential regulator of HSC homeostasis through basal activation of NF-κB. Hematopoietic-specific deletion of Traf6 resulted in impaired HSC self-renewal and fitness. Gene expression, RNA splicing, and molecular analyses of Traf6-deficient hematopoietic stem/progenitor cells (HSPCs) revealed changes in adaptive immune signaling, innate immune signaling, and NF-κB signaling, indicating that signaling via TRAF6 in the absence of cytokine stimulation and/or infection is required for HSC function. In addition, we established that loss of IκB kinase beta (IKKβ)- mediated NF-κB activation is responsible for the major hematopoietic defects observed in Traf6-deficient HSPC as deletion of IKKβ similarly resulted in impaired HSC self-renewal and fitness. Taken together, TRAF6 is required for HSC homeostasis by maintaining a minimal threshold level of IKKβ/NF-κB signaling.

Chronic immune response dysregulation in MDS pathogenesis

“…8,25 According to genetic studies, the TRAF6 dosage impacts HSC function independent of overt infection. 8,26,27 Multiple independent mechanisms contribute to hyperactivation of TLR signaling in MDS, many of which converge on TRAF6. Nevertheless insight is needed to identify the molecular consequences of TRAF6 activation in HSCs that contribute to MDS.…”

Hematopoiesis and the bacterial microbiome

“…8 Indeed, these data fit into a growing narrative that basal inflammatory signaling is required to maintain normal hematopoiesis. 8,65 Recently, Iwamura et al 9 determined that NOD1 2/2 MSCs, in contrast to wild type, are unable to produce HSPC proliferationstimulating cytokines, indicating that NOD1 signaling through MSCs is an important regulator of hematopoiesis. 9 Therefore, it is likely that MyD88/TICAM1, NOD1, and STAT1 are all involved in regulating steady-state hematopoiesis; in fact, it is possible that they all feed into the same pathway.…”

HIF-1β Positively Regulates NF-κB Activity via Direct Control of TRAF6

“…TRAF6 knockout mice are prenatal and postnatal lethal [30]. Conditional knockout models revealed essential roles for TRAF6 in a variety of immune cellular backgrounds but also in epithelial cell types [31][32][33][34], indicating how important this factor is for normal cellular homeostasis. More recently, TRAF6 was also implicated in cancer signalling, by regulating epithelial to mesenchymal transition (EMT) in colon cancer [35], DNA damage in breast cancer backgrounds [36], and involvement in autophagy responses [37].…”