Abstract
B cell life depends critically on the cytokine B cell–activating factor of the tumor necrosis factor family (BAFF). Lack of BAFF signaling leads to B cell death and immunodeficiency. Excessive BAFF signaling promotes lupus-like autoimmunity. Despite the great importance of BAFF to B cell biology, its signaling mechanism is not well characterized. We show that BAFF initiates signaling and transcriptional programs, which support B cell survival, metabolic fitness, and readiness for antigen-induced proliferation. We further identify a BAFF-specific protein kinase C β–Akt signaling axis, which provides a connection between BAFF and generic growth factor–induced cellular responses.
Highlights
The regulation of B cell life span is essential for normal immunity
We have previously shown that B cell–activating factor of the TNF family (BAFF) controls B cell survival through cytoplasmic retention of the proapoptotic kinase protein kinase C δ (PKCδ) [18]
The BAFF-induced metabolic bias toward glycolysis might be especially important for B cell survival in lymphoid organs and at inflammatory sites where oxygen tension is low compared with arterial blood [45, 46]
Summary
BAFF controls B cell metabolic fitness through a PKCβ- and Akt-dependent mechanism. Alina Patke, Ingrid Mecklenbräuker, Hediye Erdjument-Bromage, Paul Tempst, and Alexander Tarakhovsky. In addition to PKCβ translocation to the plasma membrane, BAFF promotes the association of PKCβ with Akt (Fig. 6 B) This association does not depend on PI3K activity (Fig. S4, available at http://www.jem.org/cgi/content/full/ jem.20060990/DC1), but it is functionally important, as BAFF-induced Akt phosphorylation at S473 was greatly reduced in PKCβ-deficient B cells (Fig. 6 C). The functional link between PKCβ and Akt is specific to BAFF signaling, as stimulation through the BCR induced Akt phosphorylation in PKCβ-deficient B cells at wild-type levels (Fig. 6 D). The size of the peripheral PKCβ-deficient B cell compartment falls to ف70% of wild-type levels [39], and immature B cells prevail over mature B cells in the spleen of mutant mice, as judged by surface IgM and IgD expression (Fig. 7 D) These observations suggest a partial defect in BAFF-mediated signaling and peripheral B cell maturation in the absence of PKCβ. We conclude that the BAFF-mediated regulation of NF-κB and PKCδ occurs independent of PKCβ
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