PRKCQ

Detailed Information

PRKCQ (Protein Kinase C Theta) encodes the PKCθ isoform, a member of the novel, calcium-independent PKC (nPKC) subfamily. The gene is located on human chromosome 10p15-p14, contains 18 exons, and encodes a 706-amino-acid protein with a molecular weight of approximately 82 kDa. PRKCQ protein consists of an N-terminal regulatory domain, including a C1 domain that mediates diacylglycerol (DAG) and phospholipid binding, and a C-terminal catalytic domain with serine/threonine kinase activity. Unlike calcium-dependent PKC isoforms, PRKCQ activation requires only DAG and phosphatidylserine, giving it unique functional advantages in immune cell signaling. PRKCQ expression is highly tissue-specific, enriched in T lymphocytes, skeletal muscle, platelets, and dendritic cells, while being low in most non-immune tissues. Gene regulation studies show that the PRKCQ promoter contains multiple key transcription factor binding sites (e.g., NFAT, AP-1, NF-κB), and its expression is positively regulated by T-cell receptor (TCR) activation. Epigenetic mechanisms, such as DNA methylation and histone modifications, also contribute to tissue-specific expression. Notably, the gene produces a natural antisense transcript, PRKCQ-AS1, a long non-coding RNA (lncRNA) that is dysregulated in diseases such as thyroid cancer and modulates PRKCQ function post-transcriptionally.

Figure 1. Schematic representation of PKCθ structure, showing its regulatory and catalytic domains. (Nicolle A, et al., 2021)

Biological Functions and Immune Regulatory Mechanisms

PRKCQ is a core component of TCR signaling and is indispensable for immune synapse formation and T-cell activation. Upon TCR-CD3/CD28 co-stimulation, PRKCQ is recruited to the immunological synapse center, where it phosphorylates CARD11/CARMA1 at multiple serine residues, activating the canonical NF-κB pathway. Phosphorylated CARD11 associates with lipid rafts, recruiting the BCL10-MALT1 complex and the IKK kinase complex, leading to IκB degradation and NF-κB nuclear translocation. PRKCQ also phosphorylates the mediator STK39/SPAK to activate the JUN pathway independently of the MAPK cascade. In calcium signaling, PRKCQ participates in TCR/CD28-induced NFATC1/NFATC2 transcriptional activation by modulating inositol trisphosphate (IP3) generation and calcium mobilization, influencing T-cell functional differentiation. PRKCQ selectively regulates T-cell subset differentiation, being critical for Th2 and Th17 cell development during inflammation and immune responses, while having minimal impact on Th1 cells. Mechanistically, it drives Th2 differentiation via IL-4 receptor signaling and GATA3 expression, and Th17 differentiation through RORγt activation. PRKCQ also provides survival signals by phosphorylating BAD to inhibit apoptosis and upregulating BCL-XL via NF-κB and JUN pathways, protecting T cells from activation-induced cell death.

In platelets, PRKCQ regulates downstream signals of ITGA2B, CD36, F2R/PAR1, and F2RL3/PAR4, contributing to inside-out signaling and granule secretion. By modulating the dissociation of WASP from WIPF1, PRKCQ influences Arp2/3-mediated actin nucleation and branching, regulating platelet shape change and aggregation. In metabolic regulation, PRKCQ phosphorylates IRS1 to block tyrosine phosphorylation, inhibiting insulin signaling and PI3K/AKT activation, mediating free fatty acid-induced insulin resistance. Recent studies show PRKCQ phosphorylates CCDC88A/GIV to inhibit its guanine nucleotide exchange factor activity, affecting G-protein signaling, and phosphorylates/activates LRRK1 to regulate intracellular transport via RAB protein phosphorylation, expanding the understanding of PRKCQ functions beyond immune cells.

Disease Associations and Pathological Mechanisms

PRKCQ plays a key role in multiple autoimmune disorders. In inflammatory bowel disease (IBD), genome-wide association studies (GWAS) identified PRKCQ as a susceptibility locus (IBD1). T-cell-specific PRKCQ knockout mice resist experimental colitis, associated with reduced Th17 responses and enhanced regulatory T-cell function. In rheumatoid arthritis, PRKCQ promotes synovial T-cell activation and inflammatory cytokine production (e.g., TNF-α, IL-17), contributing to joint inflammation. In systemic lupus erythematosus (SLE), aberrantly elevated PRKCQ activity in T cells leads to hyperactivation of autoreactive B cells. PRKCQ inhibitors have demonstrated efficacy in autoimmune disease models, reducing disease severity and tissue pathology. Due to PRKCQ’s selective effect on effector T cells while sparing regulatory T cells, inhibition offers a relatively targeted immunomodulatory strategy, minimizing broad immunosuppressive side effects.

In cancer immunity, PRKCQ has dual roles: enhancing T-cell antitumor responses while potentially contributing to immune evasion. In solid tumor microenvironments, PRKCQ expression affects tumor-infiltrating lymphocyte (TIL) function. High PRKCQ correlates with enhanced CD8⁺ T-cell effector activity, potentially improving immune checkpoint inhibitor efficacy. However, in certain tumors (e.g., gastrointestinal stromal tumors), PRKCQ signaling may suppress antitumor immunity by promoting immunosuppressive cytokine expression or regulatory T-cell activity. In papillary thyroid carcinoma (PTC), the antisense transcript PRKCQ-AS1 is significantly downregulated. Mechanistically, fasting or fasting-mimicking diets (FMD) upregulate PRKCQ-AS1, which interacts with IGF2BPs to stabilize PRMT7 mRNA, suppressing glycolysis and mitochondrial function. The PRKCQ-AS1/IGF2BPs/PRMT7 axis is a key metabolic reprogramming regulator in PTC, providing a novel intervention target. PRKCQ also influences tumor-associated platelet activation, potentially affecting microthrombosis and stromal remodeling in metastasis.

Targeted Therapy Strategies and Clinical Progress

PRKCQ-targeted strategies focus on small molecule inhibitors, gene silencing, and immunomodulation. Due to its central role in T-cell activation, inhibitors have been widely developed for autoimmune diseases. First-generation ATP-competitive inhibitors (e.g., AEB071) demonstrated efficacy in skin graft rejection and psoriasis but lacked selectivity. Next-generation allosteric inhibitors targeting the unique regulatory domains (e.g., C2 domain) improve isoform specificity. In cancer immunotherapy, combination strategies are emerging: PRKCQ inhibitors with PD-1/PD-L1 blockade can overcome T-cell exhaustion and enhance antitumor immunity. In thyroid cancer, targeting the PRKCQ-AS1/PRMT7 axis offers a novel approach to tumor metabolic intervention. CRISPR/Cas9-mediated PRKCQ editing in CAR-T cells can improve T-cell persistence and antitumor activity. In platelets, PRKCQ inhibition may reduce tumor-associated thrombotic events, providing additional clinical benefits for advanced cancer patients.