IFNK

Interferon kappa or IFN-kappa is a protein that in humans is encoded by the IFNK gene. Through different clinical studies, Interferon kappa has been assumed to play a role in controlling immune cell activity. It has been determined that this is a cytokine that gives cells species-specific resistance against viral infection. Interferon-stimulated response element signaling has also been hypothesized to be induced. This is because it has the ability to directly regulate the release of cytokines by monocytes and dendritic cells. It has also been discovered to bind heparin.

IFN-kappa belongs to the family of type I interferons. IFN-α, IFN-β, IFN-ε, IFN-κ, and IFN-ω are among the many cytokine subtypes that comprise the type I interferon family. A family of homologous glycoproteins known as type I interferons aids in the host's defense against viruses.

IFN-κ and IFN-ε are members of an exclusive subgroup of the type I interferon family, according to phylogenetic analysis. This is predicated on particular functional and genetic traits that distinguish IFN-κ and IFN-ε from the other type I IFNs. Crucially, IFN-κ is highly conserved in a variety of mammalian species, including mice and humans, which attests to its importance in evolution as will be expanded in sections below.

Also, the gene is on chromosome 9, close to the type I interferon cluster.

Interferon kappa (IFN-κ), a type I interferon, evolved in vertebrates as a component of the innate immune system's early reaction to viral infections. IFN-κ is a unique sublineage of the type I interferon family that differs from more widely expressed members like IFN-α and IFN-β, according to phylogenetic analyses. The human IFNK gene is found on chromosome 9 in the type I interferon gene cluster. According to comparative genomic studies, IFN-κ is conserved in a variety of placental mammals, such as ungulates, rodents, and primates, indicating that it first appeared early in the evolution of mammals. IFN-κ exhibits a very limited expression pattern in contrast to other type I interferons, especially in epithelial tissues like the skin. Its distinct distribution and evolutionary conservation emphasize its specialized function in epithelial immunity, especially at barrier surfaces such as the epidermis. The ways in which this specialization influences IFN-κ's role in host defense are still being investigated in comparative and functional studies.

By attaching itself to the heterodimeric type I interferon receptor (IFNAR), which is made up of the IFNAR1 and IFNAR2 subunits, IFN-κ carries out its biological actions. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway is triggered by this interaction. Key tyrosine residues on the intracellular domains of the receptor are phosphorylated by the associated kinases JAK1 (in combination with IFNAR2) and TYK2 (in combination with IFNAR1) upon receptor engagement. STAT1 and STAT2 dock at these phosphorylation sites, phosphorylate, dimerize, and attach to interferon regulatory factor 9 (IRF9) to form the interferon-stimulated gene factor 3 (ISGF3) complex. After moving into the nucleus, ISGF3 attaches itself to interferon-stimulated response elements (ISREs) and triggers the transcription of interferon-stimulated genes (ISGs).

IFN-κ has been demonstrated to affect secondary signaling cascades like the MAPK and PI3K/AKT pathways in addition to the canonical JAK-STAT pathway. IFN-κ can control a wider range of immune mediators, including pro-inflammatory cytokines like TNF-α and IL-6, thanks to these alternate pathways. This implies that IFN-κ signaling and larger inflammatory networks may interact. Numerous IFN-κ interaction partners, such as members of the STAT family, IRFs, and other intracellular adaptors involved in immune and antiviral responses, have been identified by bioinformatics databases like BioGRID and STRING. Nevertheless, compared to other type I interferons, its interactome is still poorly understood, showing the necessity for additional experimental verification.

Keratinocytes, the main epidermal cells, are the primary source of interferon kappa (IFN-κ), a type I interferon. IFN-κ can interact with IFNAR and start downstream signaling because it shares the characteristic alpha-helical fold of type I interferons. It is believed to be essential for localized epithelial immunity and is primarily produced by keratinocytes, the predominant cell type in the epidermis. The ability of IFN-κ to bind IFNAR with high specificity is supported by its predicted 3D structure, which was created using AlphaFold and based on UniProt ID Q9P0W0.