Protein kinase N1, a cell inhibitor of Akt kinase, has a central role in quality control of germinal center formation

Abstract

Germinal centers (GCs) are specialized microenvironments in secondary lymphoid organs where high-affinity antibody-producing B cells are selected based on B-cell antigen receptor (BCR) signal strength. BCR signaling required for normal GC selection is uncertain. We have found that protein kinase N1 (PKN1, also known as PRK1) negatively regulates Akt kinase downstream of the BCR and that this regulation is necessary for normal GC development. PKN1 interacted with and inhibited Akt1 kinase and transforming activities. Pkn1 -/- B cells were hyperresponsive and had increased phosphorylated Akt1 levels upon BCR stimulation. In the absence of immunization or infection, Pkn1-/- mice spontaneously formed GCs and developed an autoimmune-like disease with age, which was characterized by autoantibody production and glomerulonephritis. More B cells, with fewer somatic BCR gene V region hypermutations were selected in Pkn1-/- GCs. These results indicate that PKN1 down-regulation of BCR-activated Akt activity is critical for normal GC B-cell survival and selection.