TRAF6 mediates basal activation of NF-κB necessary for hematopoietic stem cell homeostasis Journal Article
| Authors: | Fang, J.; Muto, T.; Kleppe, M.; Bolanos, L. C.; Hueneman, K. M.; Walker, C. S.; Sampson, L.; Wellendorf, A. M.; Chetal, K.; Choi, K.; Salomonis, N.; Choi, Y.; Zheng, Y.; Cancelas, J. A.; Levine, R. L.; Starczynowski, D. T. |
| Article Title: | TRAF6 mediates basal activation of NF-κB necessary for hematopoietic stem cell homeostasis |
| Abstract: | Basal 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. Fang et al. identify TRAF6 as an essential regulator of hematopoietic stem cell (HSC) self-renewal and quiescence. TRAF6 preserves HSC homeostasis by maintaining a minimal threshold level of NF-κB signaling in the absence of inflammation. © 2018 The Author(s) |
| Keywords: | signal transduction; controlled study; gene deletion; nonhuman; protein function; animal cell; mouse; animal tissue; cell function; enzyme inhibition; gene expression; cell maturation; protein depletion; animal experiment; immunoglobulin enhancer binding protein; cell differentiation; cell population; stem cell; regulatory mechanism; i kappa b kinase beta; innate immunity; hematopoietic stem cell; adaptive immunity; homeostasis; toll-like receptor; hematologic disease; rna splicing; protein defect; tumor necrosis factor receptor associated factor 6; cell loss; innate immune signaling; nf-kb; priority journal; article; stem cell self-renewal; ikkbeta; traf6 |
| Journal Title: | Cell Reports |
| Volume: | 22 |
| Issue: | 5 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2018-01-30 |
| Start Page: | 1250 |
| End Page: | 1262 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2018.01.013 |
| PROVIDER: | scopus |
| PUBMED: | 29386112 |
| PMCID: | PMC5971064 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 May 2018 -- Source: Scopus |
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