Revealing cytoplasmic and nuclear activity of actin regulators during B cell diversification

It has become evident that the actin cytoskeleton functions both in the cytoplasm and nucleus.

The Wiskott-Aldrich syndrome protein (WASp) family coordinate receptor signalling to changes in the actin cytoskeleton thereby regulating cell movement, cell-to-cell communication, and gene expression.

The importance of actin dynamics in immune cells is revealed in severe primary immunodeficiency diseases with high incidence of tumors and autoimmunity caused by loss-of-function or gain-of-function mutations in WASp. This reveals that WASp activity needs to be strictly regulated for correct function of immune cells.

The understanding of WASp in the nucleus is in its infancy and raises several outstanding questions; Does WASp act as a scaffold protein for RNA polymerase transcription? Does WASp signal in the nucleus? Is the capacity to polymerize actin required for nuclear function?

We hypothesize that a dynamic actin cytoskeleton in the nucleus allows for precise movement of DNA and chromosomes over large distances.

We will examine B cells that during an infection diversify the B cell receptor in germinal centers, a process that ultimately rely on massive proliferation, DNA repair over large distances, and chromatin remodelling.

The overall goal is to reveal how nuclear WASp activity maintains genome integrity and prevents B cell transformation and to provide novel explanations and treatment strategies for primary immunodeficiency disease and B cell lymphoma.