Terminal differentiation of B cells is an essential process for the humoral immune response in vertebrates and is achieved by the concerted action of several transcription factors in response to antigen recognition and extracellular signals provided by T-helper cells. While there is a wealth of experimental data regarding the molecular and cellular signals involved in this process, there is no general consensus regarding the structure and dynamical properties of the underlying regulatory network controlling this process. We developed a dynamical model of the regulatory network controlling terminal differentiation of B cells. The structure of the network was inferred from experimental data available in the literature, and its dynamical behavior was analyzed by modeling the network both as a discrete and a continuous dynamical systems. The steady states of these models are consistent with the patterns of activation reported for the Naive, GC, Mem, and PC cell types. Moreover, the models are able to describe the patterns of differentiation from the precursor Naive to any of the GC, Mem, or PC cell types in response to a specific set of extracellular signals. We simulated all possible single loss- and gain-of-function mutants, corroborating the importance of Pax5, Bcl6, Bach2, Irf4, and Blimp1 as key regulators of B cell differentiation process. The model is able to represent the directional nature of terminal B cell differentiation and qualitatively describes key differentiation events from a precursor cell to terminally differentiated B cells.

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In the yeast Saccharomyces cerevisiae, components of the High Osmolarity Glycerol (HOG) pathway are important for the response to diverse stresses including response to endoplasmic reticulum stress (ER stress), which is produced by the accumulation of unfolded proteins in the lumen of this organelle. Accumulation of unfolded proteins may be due to the inhibition of protein N-glycosylation, which can be achieved by treatment with the antibiotic tunicamycin (Tn). In this work we were interested in finding proteins involved in the ER stress response regulated by Hog1, the mitogen activated protein kinase (MAPK) of the HOG pathway. A high gene dosage suppression screening allowed us to identify genes that suppressed the sensitivity to Tn shown by a hog1Δ mutant. The suppressors participate in a limited number of cellular processes, including lipid/carbohydrate biosynthesis and protein glycosylation, vesicle-mediated transport and exocytosis, cell wall organization and biogenesis, and cell detoxification processes. The finding of suppressors Rer2 and Srt1, which participate in the dolichol biosynthesis pathway revealed that the hog1Δ strain has a defective polyprenol metabolism. This work uncovers new genetic and functional interactors of Hog1 and contributes to a better understanding of the participation of this MAPK in the ER stress response.

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