Hematopoietic stem cell quiescence and function are controlled by the CYLD-TRAF2-p38MAPK pathway.
Bottom Line: This phenotype is dependent on the interactions between CYLD and its substrate TRAF2 (tumor necrosis factor-associated factor 2).Unexpectedly, the robust cycling of HSCs lacking functional CYLD-TRAF2 interactions was not elicited by increased NF-κB signaling, but instead by increased activation of the p38MAPK pathway.Pharmacological inhibition of p38MAPK rescued the phenotype of CYLD loss, identifying the CYLD-TRAF2-p38MAPK pathway as a novel important regulator of HSC function restricting HSC cycling and promoting dormancy.
Affiliation: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany.Show MeSH
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Mentions: To further investigate the signaling cascade downstream of CYLD–TRAF2 interactions, we first determined whether mutant CYLDex7/8−/− HSCs exhibit increased canonical NF-κB signaling. To this purpose, we analyzed the degradation of IκBα, an inhibitory kinase which sequesters NF-κB dimers in the cytosol (Baeuerle and Baltimore, 1988). Surprisingly, not only were IκBα levels the same in mutant and WT HSCs (Fig. 5 A), they were not decreased after in vitro stimulation with TNF (not depicted). In line with these results, expression of the major NF-κB signaling effectors was not increased in CYLDex7/8−/− SKLCD150+CD48−CD34− cells, with the notable exception of NFKB2 (Fig. 5 B).
Affiliation: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany.