Tyrosine Kinase 2 (TYK2) is an intracellular protein that plays a specific role in immune system signaling. It functions within cells to transmit messages that regulate the body’s immune responses. TYK2 is a component of both the innate and adaptive immune systems, the body’s natural defenses against pathogens and foreign substances.
How TYK2 Works
TYK2 acts as a cellular communicator, facilitating how cells respond to specific immune signals. It belongs to the Janus kinase (JAK) family of enzymes, which are tyrosine kinases. When immune messenger proteins, called cytokines, bind to their receptors on the cell surface, they activate TYK2 and other JAK proteins.
This activation leads to phosphorylation, where TYK2 adds phosphate groups to itself and other proteins, including STAT (Signal Transducer and Activator of Transcription) proteins. Activated STAT proteins then move into the cell’s nucleus, regulating the expression of genes involved in immune responses. TYK2 specifically relays signals from cytokines such as interleukin-12 (IL-12), interleukin-23 (IL-23), and type I interferons. These cytokines drive the function of specific immune cells, including Th1 and Th17 cells, and contribute to the innate immune response.
TYK2’s Role in Disease
Overactivity of TYK2 can contribute to various autoimmune conditions. An overactive TYK2 pathway leads to an exaggerated immune response, causing chronic inflammation and tissue damage. Genetic studies identified a naturally occurring “loss-of-function” mutation in the TYK2 gene in approximately 3-5% of the human population. This mutation is associated with a reduced risk of developing several immune-mediated disorders, suggesting TYK2’s involvement in disease pathogenesis.
TYK2 plays a significant role in conditions like psoriasis, psoriatic arthritis, systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis. In psoriasis and psoriatic arthritis, TYK2 mediates signaling for IL-12 and IL-23, which drive the development of Th1 and Th17 cells, contributing to skin inflammation and joint damage. In SLE, overactive type I interferon signaling, mediated by TYK2, promotes B-cell survival and autoantibody production, which are hallmarks of the disease.
TYK2 Inhibitors and Their Use
TYK2 inhibitors are medications designed to specifically block the activity of the TYK2 protein. These targeted therapies aim to reduce the overactive immune response in autoimmune diseases without broadly suppressing the entire immune system. Unlike other JAK inhibitors that target multiple enzymes, TYK2 inhibitors offer a more selective approach.
Deucravacitinib, for instance, is an oral, selective TYK2 inhibitor that binds to a specific regulatory domain of the TYK2 enzyme, rather than its catalytic domain. This unique mechanism achieves high selectivity for TYK2 over other JAK family members (JAK1, JAK2, JAK3), minimizing off-target effects. Deucravacitinib was approved in September 2022 for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
TYK2 inhibitors are also being investigated for other autoimmune conditions where IL-12, IL-23, and type I interferons play a significant role, such as psoriatic arthritis, lupus, and inflammatory bowel disease.