Protein kinase C theta (PKC-θ) is anenzyme that in humans is encoded by thePRKCQgene.[5] PKC-θ, a member of serine/threonine kinases, is mainly expressed inhematopoietic cells[5] with high levels inplatelets andT lymphocytes, where plays a role in signal transduction. Different subpopulations of T cells vary in their requirements of PKC-θ, therefore PKC-θ is considered as a potential target for inhibitors in the context of immunotherapy.[6]
Protein kinase C (PKC) is a family of serine- and threonine-specificprotein kinases that can be activated by thesecond messengerdiacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors forphorbol esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role. The protein encoded by this gene is one of the PKC family members. It is a calcium-independent andphospholipid-dependent protein kinase. This kinase is important forT-cell activation. It is required for the activation of the transcription factorsNF-kappaB andAP-1, and may link theT cell receptor (TCR) signaling complex to the activation of thetranscription factors.[7] PKC-θ also play a role in theapoptosis oflymphoid cells where it negatively influence and delay the aggregation ofspectrin in an early phase ofapoptosis.[8]
PKC-θ has a role in the transduction of signals inT cells, the kinase influences their activation, survival and growth. PKC-θ is important in the signal pathway integrating signals fromTCR andCD28 receptors. A junction between anAPC (anantigen presenting cell) and aT cell through theirTCR andMHC receptors forms an immunological synapse. The active PKC-θ is localized in immunological synapse ofT cells between the cSMAC (central supramolecular activation cluster containing TCR) and pSMAC (peripheral supramolecular activation cluster containingLFA-1 andICAM-1). In regulatory T cells, PKC-θ is depleted from the region of immunological synapse, whereas in effector T cells, PKC-θ is present.[6] As a result of co-stimulation by CD28 and TCR, PKC-θ is sumoylated bySUMO1 predominantly on the sites Lys325 and Lys506. Sumoylation is important because of forming of the immunological synapse.[9] Subsequently, PKC-θ phosphorylates SPAK (STE20/SPS1-related, proline alanine-rich kinase) that activates the transcription factorAP-1 (activating protein-1). PKC-θ also initiates the assembly of proteinsCarma-1,Bcl-10 andMalt-1 by phosphorylation ofCarma-1. This complex of three proteins activates the transcription factor NF-κB (nuclear factor-κB). Furthermore, PKC-θ plays a role in the activation of transcription factor NF-AT (nuclear factor of activated T cells).[10] Thus, PKC-θ promotes inflammation in effector T cells.[6] PKC-θ plays a role in the activation of ILC2 and contribute to the proliferation of Th2 cells.[11] The kinase PKC-θ is crucial for function ofTh2 andTh17.[6] Moreover, PKC-θ can translocate itself to the nucleus and by phosphorylation of histones increases the accessibility of transcriptional-memory-responsive genes in memory T cells.[12] PKC-θ plays a role in anti-tumor activity ofNK cells. It was observed that in mice without PKC-θ,MHCI-deficient tumors are more often.[13]
Properties of PKC-θ make PKC-θ a good target for therapy in order to reduce harmful inflammation mediated by Th17 (mediating autoimmune diseases) or by Th2 (causing allergies)[11] without diminishing the ability of T cells to get rid of viral-infected cells. Inhibitors could be used in T-cell mediated adaptive immune responses. Inhibition of PKC-θ downregulates transcription factors (NF-κB,NF-AT) and cause lower production ofIL-2. It was observed that animals without PKC-θ are resistant to some autoimmune diseases.[6] PKC-θ could be a target of inhibitors in the therapy ofallergies.
The problem is that inhibitors of PKC-θ targeting catalytic sites may have toxic effects because of low specificity (catalytic sites among PKCs are very similar).Allosteric inhibitors have to be more specific to concrete isoforms of PKC.[6] s.
^Wang XD, Gong Y, Chen ZL, Gong BN, Xie JJ, Zhong CQ, et al. (2015). "TCR-induced sumoylation of the kinase PKC-θ controls T cell synapse organization and T cell activation".Nature Immunology.16 (11):1195–1203.doi:10.1038/ni.3259.ISSN1529-2916.PMID26390157.S2CID21498259.
^Zeng Q, Luo P, Gu J, Liang B, Liu Q, Zhang A (2017). "PKC θ-mediated Ca 2+ /NF-AT signalling pathway may be involved in T-cell immunosuppression in coal-burning arsenic-poisoned population".Environmental Toxicology and Pharmacology.55:44–50.doi:10.1016/j.etap.2017.08.005.PMID28823652.
^Jimenez JM, Boyall D, Brenchley G, Collier PN, Davis CJ, Fraysse D, et al. (2013). "Design and optimization of selective protein kinase C θ (PKCθ) inhibitors for the treatment of autoimmune diseases".Journal of Medicinal Chemistry.56 (5):1799–1810.doi:10.1021/jm301465a.PMID23398373.
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