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.humoral immunity | immunoglobulin | affinity maturation

Crystal Structures of PRK1 in Complex with the Clinical Compounds Lestaurtinib and Tofacitinib Reveal Ligand Induced Conformational Changes

“…PRK1 and PRK2 have been shown to phosphorylate HDAC5, HDAC7 and HDAC9 with the effect of inhibiting nuclear localization [5]. A further role for PRK1 in the development of germinal centers downstream of the B-cell receptor has also been reported [6]. Clinically, PRK1 has been shown to be overexpressed in ovarian serous carcinoma [7].…”

Structure of an SspH1-PKN1 Complex Reveals the Basis for Host Substrate Recognition and Mechanism of Activation for a Bacterial E3 Ubiquitin Ligase

“…Macrophages from MR knockout mice exhibit decreased classical activation (antimicrobial functions) and increased alternative activation (tissue repair functions), leading to reduced inflammation (38). Second, PKN1 is a negative regulator of Akt, such that PKN1 knockout mice display increased basal Akt activation, resistance to cell death signals in B cells, and concomitant autoimmune phenotypes (39). With respect to infection, the intracellular growth of pathogenic Salmonella depends on activation of Akt (40).…”

Evasion of affinity-based selection in germinal centers by Epstein–Barr virus LMP2A

“…Both LMP2A CD19 and LMP2A AID mice exhibited hyperimmunoglobulinemia (Fig. S7), which often is associated with autoantibody production in murine autoimmunity models (31,48). Likewise, autoantibody production often is observed in IM patients (49,50).…”