PROSITE documentation PDOC52075

Interferon (IFN) type-I, -II, -III and -IV families profiles

The interferons (IFNs) are a subset of class II α-helical cytokines that have a variety of functions, most notably conferring a viral-resistant state to receptive cells. They play a major role in orchestrating the innate immune response toward viruses in vertebrates, and their defining characteristic is their ability to induce an antiviral state in responsive cells. IFNs are characterized by activities that vary over time and can lead to opposing outcomes. IFNs have protective roles during bacterial, viral, and fungal infections but can also drive numerous inflammatory and autoimmune diseases. Beyond their function during infections, IFNs have emerged as key regulators of the immune system in essentially every human disease context, exerting functions even in processes that go beyond classical immunity, such as behavior, memory formation, and neurodegeneration [1,2,3,4].

IFNs have been reported in a multitude of species, from bony fish to mammals. Based on their genomic structures, receptors and biological functions, IFNs are divided into four types, namely type I, type II, type III, and type IV IFNs. IFNs are proteins of less than 210 amino acids, with low amino acid identity between the different families [2,4,5].

Type I IFNs are widespread in vertebrates from fish to mammals and include the IFN-α family of subtypes, a single IFN-β and several poorly defined single gene products (IFN-epsilon, IFN-tau, IFN-kappa, IFN-omega, IFN-delta and IFN-zeta. Type I IFNs have diverse effects on innate and adaptive immune cells during infection with viruses, bacteria, parasites and fungi, directly and/or indirectly through the induction of other mediators. Type I IFNs are important for host defence against viruses [6].

Tetrapods possess only a single copy of type II IFN gene, called IFN-γ, which is mainly involved in immune regulation. In general, teleost fish are reported to have the composition of two type II IFN genes, including IFN-γ and IFN-γ-related (IFN-γrel), except that two IFN-γ genes were identified in channel catfish (named as IFN-γ2a and IFN-γ2b) and in ginbuna crucian carp (IFN-γ1 and IFN-γ2), and two IFN-γrel genes were also reported in ginbuna crucian carp (IFN-γrel1 and IFN-γrel2). Three members of type II IFN family, named as IFN-γ-like, IFN-γ and IFN-γrel, were identified in the osteoglossiform fish, arapaima. IFN-γ does possess some antiviral activity but is mainly an immunomodulatory cytokine acting on leukocytes [2,7].

Type III IFNs, commonly known as interferon lambda (IFNL or IFN-lambda), have been reported in mammals, birds, reptiles, amphibians, and cartilaginous fish. IFN-IIIs include IFN-lambda1-3 (also known as interleukin [IL]-29, IL-28A, and IL-28B) and IFN-lambda4 (only IFN-lambda2 and IFN-lambda3 exist in mice). They play a crucial role as gatekeepers, particularly in safeguarding mucosal epithelial cells [4,8,9].

IFN-upsilon (IFNU), the type IV IFN, is found in jawed vertebrates ranging from cartilaginous fish to primitive mammals. It differs from type I, II, and III IFNs in consideration of sequence feature, gene locus, phylogeny, and receptor complex. IFN-upsilon proteins in vertebrates were reported to contain conserved sequence, CXXXXX(W/L) at N-terminus, being different from other known three types of IFNs [10,11,12].

Types I, III, and IV IFNs each consisted of five α-helices, while type II consisted of six α-helices labelled as A-F (see <PDB:3SE3>, <PDB:1EKU> and <PDB:3HHC>) [5].

The profiles we developed cover respectively the entire IFN type-I, -II, -III and -IV families.