Journal article
Context-Specific BAFF-R Signaling by the NF-κB and PI3K Pathways
Cell reports (Cambridge), Vol.5(4), pp.1022-1035
11/27/2013
DOI: 10.1016/j.celrep.2013.10.022
PMCID: PMC3887557
PMID: 24239354
Abstract
BAFF is a soluble factor required for B cell maturation and survival. BAFF-R signals via the noncanonical NF-κB pathway regulated by the TRAF3/NIK/IKK1 axis. We show that deletion of Ikk1 during early B cell development causes a partial impairment in B cell maturation and BAFF-dependent survival, but inactivation of Ikk1 in mature B cells does not affect survival. We further show that BAFF-R employs CD19 to promote survival via phosphatidylinositol 3-kinase (PI3K), and that coinactivation of Cd19 and Ikk1 causes a profound block in B cell maturation at the transitional stage. Consistent with a role for PI3K in BAFF-R function, inactivation of PTEN mediates a partial rescue of B cell maturation and function in Baff−/− animals. Elevated PI3K signaling also circumvents BAFF-dependent survival in a spontaneous B cell lymphoma model. These findings indicate that the combined activities of PI3K and IKK1 drive peripheral B cell differentiation and survival in a context-dependent manner.
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•IKK1 loss creates a bottleneck, but not an impasse, in transitional B cell maturation•Acute BAFF-dependent survival of mature B cells is IKK1 independent•Coinactivation of Cd19 and Ikk1 prevents the generation of mature B cells•Activation of the PI3K pathway partially rescues B cell defects in Baff−/− mice
BAFF is an essential survival factor for B cell homeostasis. BAFF-R signaling is thought to depend mainly on the IKK1-dependent noncanonical NF-κB pathway. Rickert and colleagues now show that although this pathway is important for the transitional stage of B cell development, it is not required for the acute survival of mature recirculating B cells responding to BAFF. They also provide evidence that activation of the phosphatidylinositol 3-kinase pathway is likely of key importance for BAFF-R function.
Details
- Title: Subtitle
- Context-Specific BAFF-R Signaling by the NF-κB and PI3K Pathways
- Creators
- Julia Jellusova - Program on Inflammatory Diseases, Infectious and Inflammatory Diseases Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USAAna V Miletic - Program on Inflammatory Diseases, Infectious and Inflammatory Diseases Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USAMatthew H Cato - Program on Inflammatory Diseases, Infectious and Inflammatory Diseases Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USAWai-Wai Lin - Graduate Program in Immunology, The University of Iowa and the VA Medical Center, Iowa City, IA 52242, USAYinling Hu - Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21701, USAGail A Bishop - Graduate Program in Immunology, The University of Iowa and the VA Medical Center, Iowa City, IA 52242, USAMark J Shlomchik - Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USARobert C Rickert - Program on Inflammatory Diseases, Infectious and Inflammatory Diseases Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.5(4), pp.1022-1035
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.celrep.2013.10.022
- PMID
- 24239354
- PMCID
- PMC3887557
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Language
- English
- Date published
- 11/27/2013
- Academic Unit
- Microbiology and Immunology; President
- Record Identifier
- 9984002396302771
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