PAX5 ability to repress BLIMP1 is phosphorylation-dependent

When a B cell starts releasing antibodies on the large scale it undergoes the sequence of deep morphological and physiological changes. It expands its cytoplasm and switches on the machinery that lets it cope with the enhanced protein production in preparation to professional antibody secretion. On the molecular level this transition it governed by the onset in expression of certain transcription factors whereas other transcription factors are being switched off. The main players in the transformation of a B cell to a plasma cell are transcription factors PAX5 and BLIMP1. PAX5 is expressed in all B cells except the plasma cell stage while BLIMP1 holds the position of chief regulator that opens the way to antibody secreting cell phenotype. Additionally, it is known that PAX5 represses BLIMP1 and that this repression can be relieved by signaling through BCR. I have read the publication which examines details of the interactions between PAX5, BLIMP1 and the signaling relay activated by BCR stimulation.

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The report’s leading theme is the analysis how the phosphorylation status of PAX5 may influence its ability to repress BLIMP1 promoter. Initially authors identify two residues in PAX5 sequence that can be phosphorylated by ERK kinase which is a part of cascade that transmits the signal originating from BCR. Since the repression competence of PAX5 may be dictated by its phosphorylation state investigators test whether it is possible to activate Blimp-1 promoter when PAX5 is modified to become unresponsive to ERK-driven phosphorylation. To this end they demonstrate that the BCR activation starts off the signaling cascade which terminates with PAX5 phosphorylation by ERK and that the phosphorylated PAX5 is unable to maintain the repression of BLIMP1 promoter. However, the mutated form of PAX5 with its phosphorylation sites replaced by alanine substitutions continues the transcriptional repression of Blimp-1 regardless of BCR activation. Thus the signal at BCR may initiate the plasmacytic differentiation because it changes PAX5 phosphorylation status.

The discussed publication studies the molecular events only and due to a number of technical limitations (see the discussion chapter in the original paper) it does not attempt to translate its findings to the actual immune response (e.g. whether the same PAX5 modifications may influence plasma cell counts). Why do I think it is interesting, though? The answer is I have just read another paper published by Mark Shlomchik’s group (B Cell Receptor Signal Transduction in the GC Is Short-Circuited by High Phosphatase Activity. Science; 2012. 336: 1178-81). That paper examines the extend of BCR signaling during the germinal center reaction and finds it very limited.

According to authors in GC B cells the phosphorylation level of several components belonging to BCR signaling cascade is diminished compared to non-GC B cells. Such reduction is due to the enhanced phosphatase activity which abolishes signals that could be potentially transmitted downstream when BCR is activated during germinal center reaction. Moreover, the specific to B cells inactivation of SHP-1 phosphatase decreases the GC B cell frequency which indicates that the temporal inhibition of BCR signaling may be actually vital for the proper GC maintenance.

The key findings of these two papers (1) The signaling at BCR may open the way to plasma cell phenotype through phosphorylation cascade which completes with PAX5-mediated relieve of BLIMP1 repression. (2) In GC B cells BCR signaling is limited because of high phosphatase activity make a lot sense when combined together. Germinal centers are anatomical sites where B cells undergo antigen-driven affinity maturation and the GC reaction which is terminated too early would compromise the quality of immune response. It looks like the stimulation at BCR may be able to set off the change in the transcription factor architecture (through the phosphorylation-dependent mechanism) that could promote the immediate plasmacytic differentiation. Therefore the temporal modulation of BCR signaling during GC reaction could be crucial because it would ensure enough time to generate high affinity antibody response. Is this the case? Maybe it is.

Yasuda T, Hayakawa F, Kurahashi S, Sugimoto K, Minami Y, Tomita A, & Naoe T (2012). B cell receptor-ERK1/2 signal cancels PAX5-dependent repression of BLIMP1 through PAX5 phosphorylation: a mechanism of antigen-triggering plasma cell differentiation. Journal of immunology (Baltimore, Md. : 1950), 188 (12), 6127-34 PMID: 22593617


Borrelia burgdorferi – the master manipulator


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