mTOR-Dependent and Independent Survival Signaling by PI3K in B Lymphocytes

Peripheral B lymphocyte survival requires the B cell receptor (BCR) and B cell activating factor (BAFF) binding to its receptor (BAFF-R). Deletion of the BCR, or its signal transducing chaperone Igβ, leads to rapid loss of mature B cells, indicating that signals initiated at the BCR are crucial for...

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Vydáno v:PloS one Ročník 11; číslo 1; s. e0146955
Hlavní autoři: Kaileh, Mary, Vazquez, Estefania, MacFarlane, Alexander W., Campbell, Kerry, Kurosaki, Tomohiro, Siebenlist, Ulrich, Sen, Ranjan
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Public Library of Science 19.01.2016
Public Library of Science (PLoS)
Témata:
1-Phosphatidylinositol 3-kinase
Animals
Antigens
Apoptosis
B cells
B-Cell Activating Factor - pharmacology
B-Cell Activation Factor Receptor - metabolism
B-cell receptor
B-Lymphocytes - cytology
B-Lymphocytes - metabolism
BLyS protein
Bone marrow
Cancer
Cell Survival
Cells, Cultured
Cellular signal transduction
Clonal deletion
Gene expression
Genetic aspects
Homeostasis
Immunology
Infectious diseases
Kinases
Laboratories
Lymphocyte receptors
Lymphocytes
Lymphocytes B
Lymphoma
Mcl-1 protein
Medical research
Mice
Molecular biology
Myeloid Cell Leukemia Sequence 1 Protein - genetics
NF-kappa B p52 Subunit - genetics
Phosphatidylinositol 3-Kinases - metabolism
Physiological aspects
Post-transcription
Protein kinases
Proto-Oncogene Proteins c-bcr - metabolism
Signal Transduction
Signaling
Spleen
Survival
TOR protein
TOR Serine-Threonine Kinases - metabolism
United States
Japan
ISSN:1932-6203, 1932-6203
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Popis
Shrnutí:Peripheral B lymphocyte survival requires the B cell receptor (BCR) and B cell activating factor (BAFF) binding to its receptor (BAFF-R). Deletion of the BCR, or its signal transducing chaperone Igβ, leads to rapid loss of mature B cells, indicating that signals initiated at the BCR are crucial for B cell survival. BAFF or BAFF-R deficiency also significantly reduces the numbers of mature B cells despite normal BCR expression. Together, these observations indicate that continued BCR and BAFF-R signaling are essential for the survival of mature resting B cells in the periphery. Here we demonstrate that tonic BCR signals up-regulate p100 (Nfkb2) as well as Mcl-1 protein expression at a post-transcriptional level via a PI3K-dependent pathway. p100 expression is mTOR-independent, whereas Mcl-1 expression is mTOR-dependent. BAFF treatment further elevated Mcl-1 levels by an mTOR-independent pathway, while consuming p100. Accordingly, Mcl-1 induction by BAFF is abrogated in Nfkb2-/- B cells. We propose that the cumulative effects of the BCR and BAFF-R signaling pathways increase Mcl-1 levels beyond the threshold required for B cell survival.
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Competing Interests: The authors have declared that no competing interests exist.
Conceived and designed the experiments: MK RS. Performed the experiments: MK. Analyzed the data: MK RS. Contributed reagents/materials/analysis tools: EV US. Wrote the paper: MK RS. Provided mice of various genotypes as mentioned in the manuscript: EV AM KC TK US.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0146955