Protein Kinase C δ: a Gatekeeper of Immune Homeostasis

Abstract

Human autoimmune disorders present in various forms and are associated with a life-long burden of high morbidity and mortality. Many different circumstances lead to the loss of immune tolerance and often the origin is suspected to be multifactorial. Recently, patients with autosomal recessive mutations in PRKCD encoding protein kinase c delta (PKCδ) have been identified, representing a monogenic prototype for one of the most prominent forms of humoral systemic autoimmune diseases, systemic lupus erythematosus (SLE). PKCδ is a signaling kinase with multiple downstream target proteins and with functions in various signaling pathways. Interestingly, mouse models have indicated a special role of the ubiquitously expressed protein in the control of B-cell tolerance revealed by the severe autoimmunity in Prkcd−/− knockout mice as the major phenotype. As such, the study of PKCδ deficiency in humans has tremendous potential in enhancing our knowledge on the mechanisms of B-cell tolerance.

Metabolic Regulation of the Immune Humoral Response

“…Protein kinase-C beta (PKCβ), which is activated both by the BCR via phospholipase C-γ2 (PLC-γ 2), promotes anti-Ig-induced increases in glycolytic flux (Blair et al, 2012). Intriguingly, PKCδ-deficient B cells exhibit normal BCR-activated glycolysis (Blair et al, 2012), consistent with a number of findings indicating that PKCδ and β have distinct and in some cases opposing roles in B cell activation (Salzer et al, 2016). PKCβ also is downstream from PI3K, which acts through PDK1 and mTOR complex 2 (mTORC2) to enhance PKC as well as AKT (Das et al, 2016; Lee et al, 2010; Lee et al, 2013).…”

Novel insights into the host immune response of chicken Harderian gland tissue during Newcastle disease virus infection and heat treatment

“…A single gene, protein kinase C delta (PRKCD), was the only gene that was differentially expressed across all three time points in Fayoumi. PRKCD encodes for a protein kinase that is a regulator of cell apoptosis and is often highly expressed in lymphoid tissue in humans [ 25 ]. A limited early response in both Fayoumi and Leghorn lines occurred at 2 dpi, although the Leghorn line had relatively more DEGs than Fayoumi.…”

Protein kinase C: perfectly balanced

“…As such, JSLE patients often develop B-cell lymphomas (Bernatsky et al 2005). Four LOF mutations have been identified in the disease (Salzer et al 2016): an invariant Gly (G248) on one of the ligand-binding loops of the C1B domain is mutated to Ser in one patient with a JSLE-like disorder, a biallelic splice-site mutation causing the absence of protein product was identified in a patient with severe autoimmunity (Salzer et al 2013), an invariant Gly (G510) in the highly conserved activation loop of AGC kinases is mutated to Ser in three siblings with JSLE, and an Arg in a segment preceding the conserved PXXP motif of the C-terminal tail is mutated to Trp in a patient with autoimmune lymphoproliferative syndrome (Kuehn et al 2013). Somatic mutations in the latter residue (including to Trp) have also been identified in three different colorectal tumors (cBioPortal; (Gao J et al 2013)).…”