title: Notch-regulated periphery B cell differentiation involves suppression of E protein function.
abstract: Notch signaling pathway plays important roles in promoting the generation of marginal zone (MZ) B cells at the expense of follicular (FO) B cells during periphery B cell maturation, but the underlying molecular mechanisms are not well understood. We hypothesize that Notch favors the generation of MZ B cells by downregulating E protein activity. In this study, we demonstrated that expression of Id2 and ankyrin-repeat SOCS box-containing protein 2 was elevated in MZ B cells and by Notch signaling. Id2 inhibits the DNA binding activity of E proteins, whereas ankyrin-repeat SOCS box-containing protein 2 facilitates E protein ubiquitination. Next, we examined the phenotypes of splenic B cells in mice expressing constitutively active Notch1 and/or two gain-of-function mutants of E proteins that counteract Id2-mediated inhibition or Notch-induced degradation. We found that upregulation of E proteins promoted the formation of FO B cells, whereas it suppressed the maturation of MZ B cells. In contrast, excessive amounts of Notch1 stimulated the differentiation of MZ B cells and inhibited the production of FO B cells. More interestingly, the effects of Notch1 were reversed by gain of E protein function. Furthermore, high levels of Bcl-6 expression in FO B cells was shown to be diminished by Notch signaling and restored by E proteins. In addition, E proteins facilitated and Notch hindered the differentiation of transitional B cells. Taken together, it appears that Notch regulates peripheral B cell differentiation, at least in part, through opposing E protein function.
authors.affiliation: Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Sun
mesh_terms: D000818:Animals; D017089:Ankyrin Repeat; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; C497762:Notch1 protein, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D051881:Receptor, Notch1; D018078:Receptors, Prostaglandin E; C491409:Socs2 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins