The Yin and Yang of Protein Kinase C-theta (PKCθ)

Abstract

Protein kinase C-θ (PKCθ) is a PKC family member expressed predominantly in T lymphocytes, and extensive studies addressing its function have been conducted. PKCθ is the only T cell-expressed PKC that localizes selectively to the center of the immunological synapse (IS) following conventional T cell antigen stimulation, and this unique localization is essential for PKCθ-mediated downstream signaling. While playing a minor role in T cell development, early in vitro studies relying, among others, on the use of PKCθ-deficient (Prkcq−/−) T cells revealed that PKCθ is required for the activation and proliferation of mature T cells, reflecting its importance in activating the transcription factors NF-κB, AP-1 and NFAT, as well as for the survival of activated T cells. Upon subsequent analysis of in vivo immune responses in Prkcq−/− mice, it became clear that PKCθ has a selective role in the immune system: It is required for experimental Th2 and Th17-mediated allergic and autoimmune diseases, respectively, and for alloimmune responses, but is dispensable for protective responses against pathogens and for graft-vs.-leukemia responses. Surprisingly, PKCθ was recently found to be excluded from the IS of regulatory T cells (Tregs) and to negatively regulate their suppressive function. These attributes of PKCθ make it an attractive target for catalytic or allosteric inhibitors that are expected to selectively suppress harmful inflammatory and alloimmune responses without interfering with beneficial immunity to infections. Early progress in developing such drugs is being made, but additional studies on the role of PKCθ in the human immune system are urgently needed.

Chemical proteomic map of dimethyl fumarate–sensitive cysteines in primary human T cells

“…Among these proteins were several with important immune functions (table S1). DMF-sensitive cysteine residues were found, for example, in multiple proteins that are either components or regulators of the NF-κB signaling pathway, including inhibitor of κB (IκB) kinase β (IKKβ or IKBKB) (24), protein kinase C-θ (PKCθ or PRKCQ) (25, 26), and tumor necrosis factor α–induced protein 3 (TNFAIP3, also known as A20) (27, 28) (table S1). Consistent with these, and potentially other, sites of DMF action being within the NF-κB pathway (19), we found that DMF blocked the nuclear translocation of p65 in anti-CD3/CD28–stimulated human T cells (fig.…”

PKCθ-regulated signalling in health and disease

“…It is assumed that the WIP-WASP complex is associated with a Crk adaptor protein, which can interact with a TCRζ chain-bound activated ZAP-70 and thereby bring WIP into close physical proximity to the IS-residing PKCθ [24][25][26]. PKCθ was reported to physically associate with several other proteins, including 14-3-3τ , Cbl, Lck, Akt, moesin and PKC-interacting cousin of thioredoxin (PICOT) ( [9,10,27,28] and references therein), which may serve as substrates or upstream kinases of PKCθ, or regulators of its activity and/or subcellular distribution.…”

“…The interest in PKCθ as a potential drug target has increased over time as it has become clear that it is essential for the induction of harmful inflammatory responses, including Th2-mediated allergies, Th17-mediated autoimmune diseases, graft compared with host disease and allograft rejection, but is dispensable for beneficial responses, including Th1-and cytotoxic T-lymphocyte (CTL)-mediated antiviral responses and graft compared with leukaemia response following bone marrow allotransplantation (reviewed in [10]). …”

“…However, upon cell activation, it translocates to the plasma membrane where it interacts with diacylglycerol (DAG), a transient product of phospholipase Cγ 1-mediated hydrolysis of the plasma membrane phospholipid, phosphatidylinositol 3,4-bisphosphate (reviewed in [9,10]). …”

“…PKCθ is a key modulator of T-cell receptor (TCR) signalling and an essential regulator of T-cell activation and survival [10]. It is involved in the formation of a functional immunological synapse (IS) at the T-cell-antigenpresenting cell (APC) contact area, and the directional release of cytokines and cytolytic factors from cytotoxic T-cells…”