TRAF6 Mediates Basal Activation of NF-?B Necessary for Hematopoietic Stem Cell Homeostasis.

ABSTRACT: Basal nuclear factor ?B (NF-?B) activation is required for hematopoietic stem cell (HSC) homeostasis in the absence of inflammation; however, the upstream mediators of basal NF-?B signaling are less well understood. Here, we describe TRAF6 as an essential regulator of HSC homeostasis through basal activation of NF-?B. 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-?B 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 I?B kinase beta (IKK?)-mediated NF-?B activation is responsible for the major hematopoietic defects observed in Traf6-deficient HSPC as deletion of IKK? similarly resulted in impaired HSC self-renewal and fitness. Taken together, TRAF6 is required for HSC homeostasis by maintaining a minimal threshold level of IKK?/NF-?B signaling.

SUBMITTER: Fang J 

PROVIDER: S-EPMC5971064 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature