cAMP/PKA mediated signaling in B cell metabolism and function.
Final Report Abstract
B cells are an important component of the immune system and help us fight pathogens. However, aberrant B cell signaling can contribute to the development of various diseases including autoimmune disorders or cancer. A better understanding of the role different signaling molecules play in B cells can provide new targets to manipulate B cell function and to treat B cell derived diseases. Cyclic adenosine monophosphate (cAMP) is a ubiquitous signaling molecule known to activate various proteins including protein kinase A (PKA). It has been reported before that PKA plays a role in regulating germinal center (GC) B cell responses by enhancing immunoglobulin isotype switching and by inhibiting glycogen synthase kinase (GSK3) activity. Beyond these findings, the exact role of cAMP/PKA signaling in B cell development, maturation and differentiation was not known. In this project we could demonstrate that cAMP/PKA signaling plays a context dependent role in B cells. We found that cAMP treatment significantly reduced mitochondrial oxygen consumption, cell survival and proliferation of anti-IgM stimulated B cells. The negative effects of cAMP on anti-IgM stimulated cells could partially be rescued by providing the cells with pro-survival signals. Using a mouse model in which the cAMP target PKA is hyperactivated in B cells, we could show that PKA activation alone is sufficient to reduce survival of anti-IgM stimulated cells. Although GSK3 has been reported to be inhibited by PKA, we found PKA hyperactivation and GSK3 inhibition to have fundamentally different effects on B cell signaling, metabolism and function of normal and malignant B cells. In summary, we have provided further insight into the role cAMP/PKA signaling plays in B cells.
Publications
-
Accumulation of the GSK3 target protein β-catenin is lethal for B cell precursors and malignant B cells.
Jumaa, Huda; Kistner, Klaus M.; Setz, Corinna; Taketo, M. Mark; Jumaa, Hassan & Jellusova, Julia
-
B cells are addicted to immunoglobulin production in the ER.
Caganova, Marieta; Taskiran, Hakan; Zong, Yue; Zach, Andreas; Kabrani, Eleni; Schmidt, Kristin; Goffing, Paul; Jellusova, Julia & Rajewsky, Klaus
