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Regulation of late B cell differentiation by intrinsic IKKalpha-dependent signals.

ABSTRACT: NF-kappaB-inducing kinase (NIK)-mediated IKKalpha phosphorylation activates the alternative NF-kappaB pathway, which is characterized by nuclear translocation of p52:RelB heterodimers. This alternative pathway is initiated by a select few receptors, including LT-betaR, BAFF-R, and CD40. Although NIK, IKKalpha, and p52 are all critical regulators of LT-betaR signaling in stromal cells during humoral immune responses, lymphocytes require NIK, but not p52, for optimal Ig production. This disparity suggests that NIK possesses critical cell-type-specific functions that do not depend on NF-kappaB. Here we use mice bearing targeted mutations of the IKKalpha activation loop Ser(176/180) (IKKalpha(AA)) to address the B cell-intrinsic functions of NIK-IKKalpha signaling in vivo. We find that IKKalpha(AA) B cells mount normal primary antibody responses but do not enter germinal centers. This defect likely derives from ineffective early T-B cell collaboration and leads to impaired generation of humoral memory and relatively short-lived, low-affinity antibody production. Our findings contrast with those obtained by using p52(-/-) B cells, which mount normal Ig responses, and alymphoplasia (NIK mutant) B cells, which produce very little primary Ig. Thus, the NIK-IKKalpha-p52 axis is not as linear and exclusive as previous studies suggest, and IKKalpha possesses critical NF-kappaB-independent functions in B cells.

SUBMITTER: Mills DM

PROVIDER: S-EPMC1851084 | biostudies-other | 2007 Apr

REPOSITORIES: biostudies-other

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Regulation of late B cell differentiation by intrinsic IKKalpha-dependent signals.

Mills David M DM Bonizzi Giuseppina G Karin Michael M Rickert Robert C RC

Proceedings of the National Academy of Sciences of the United States of America 20070402 15

NF-kappaB-inducing kinase (NIK)-mediated IKKalpha phosphorylation activates the alternative NF-kappaB pathway, which is characterized by nuclear translocation of p52:RelB heterodimers. This alternative pathway is initiated by a select few receptors, including LT-betaR, BAFF-R, and CD40. Although NIK, IKKalpha, and p52 are all critical regulators of LT-betaR signaling in stromal cells during humoral immune responses, lymphocytes require NIK, but not p52, for optimal Ig production. This disparity ...[more]

PMID: 17404218

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Project description:Leishmania are obligatory intracellular parasitic protozoa that cause a wide range of diseases in humans, cycling between extracellular promastigotes in the mid-gut of sand flies and intracellular amastigotes in the phagolysosomes of mammalian macrophages. Although many of the molecular mechanisms of development inside macrophages remain a mystery, the development of a host-free system that simulates phagolysosome conditions (37 °C and pH 5.5) has provided new insights into these processes. The time course of promastigote-to-amastigote differentiation can be divided into four morphologically distinct phases: I, signal perception (0-5 h after exposure); II, movement cessation and aggregation (5-10 h); III, amastigote morphogenesis (10-24 h); and IV, maturation (24-120 h). Transcriptomic and proteomic analyses have indicated that differentiation is a coordinated process that results in adaptation to life inside phagolysosomes. Recent phosphoproteomic analysis revealed extensive differences in phosphorylation between promastigotes and amastigotes and identified stage-specific phosphorylation motifs. We hypothesized that the differentiation signal activates a phosphorylation pathway that initiates Leishmania transformation, and here we used isobaric tags for relative and absolute quantitation to interrogate the dynamics of changes in the phosphorylation profile during Leishmania donovani promastigote-to-amastigote differentiation. Analysis of 163 phosphopeptides (from 106 proteins) revealed six distinct kinetic profiles; with increases in phosphorylation predominated during phases I and III, whereas phases II and IV were characterized by greater dephosphorylation. Several proteins (including a protein kinase) were phosphorylated in phase I after exposure to the complete differentiation signal (i.e. signal-specific; 37 °C and pH 5.5), but not after either of the physical parameters separately. Several other protein kinases (including regulatory subunits) and phosphatases also showed changes in phosphorylation during differentiation. This work constitutes the first genome-scale interrogation of phosphorylation dynamics in a parasitic protozoa, revealing the outline of a signaling pathway during Leishmania differentiation. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (identifier PXD000671). Data can be viewed using ProteinPilot™ software.

Dataset Information

Regulation of late B cell differentiation by intrinsic IKKalpha-dependent signals.

Publications

Regulation of late B cell differentiation by intrinsic IKKalpha-dependent signals.

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