Shared and Unique Features of Human Interferon-Beta and Interferon-Alpha Subtypes

Abstract

Type I interferons (IFN-I) were first discovered as an antiviral factor by Isaacs and Lindenmann in 1957, but they are now known to also modulate innate and adaptive immunity and suppress proliferation of cancer cells. While much has been revealed about IFN-I, it remains a mystery as to why there are 16 different IFN-I gene products, including IFNβ, IFNω, and 12 subtypes of IFNα. Here, we discuss shared and unique aspects of these IFN-I in the context of their evolution, expression patterns, and signaling through their shared heterodimeric receptor. We propose that rather than investigating responses to individual IFN-I, these contexts can serve as an alternative approach toward investigating roles for IFNα subtypes. Finally, we review uses of IFNα and IFNβ as therapeutic agents to suppress chronic viral infections or to treat multiple sclerosis.

Keywords: human; interferon-alpha; interferon-beta; interferon-omega; primate; type I interferon.

Figure 1

Gene map of the human IFN-I gene cluster. Above the line are pseudogenes for IFNν (NNP), IFNα subtypes, IFNω, and for the functional KLHL9 gene. On the line are the 17 functional type I IFN genes. Genes for IFNα subtypes are labeled only by number.

Figure 2

Canonical and noncanonical IFN signaling. IFN first binds to IFNAR2 after which the IFN/IFNAR2 binary complex recruits IFNAR1 to form a functional ternary signaling complex (IFN/IFNAR1/IFNAR2). Following that, Jak1 and Tyk2 kinases, which are pre-associated with IFNAR2 and IFNAR1 respectively, phosphorylate each other and tyrosine residues on each receptor (red dots) upon which STAT (signal transducers and activators of transcription) family members dock. Canonical signaling consists of a trimer of pSTAT1, pSTAT2, and IRF9 which is referred to as ISGF3 (interferon-stimulated gene factor 3). ISGF3 translocates to the nucleus to bind ISRE (interferon-stimulated response elements) to stimulate transcription of robust ISGs. There are many non-canonical signaling pathways, one of which is formation of phosphorylated STAT1 homodimers that bind to GAS (gamma activation site) promoter elements. k_a and k_d are association and disassociation rates, respectively. K_D is the equilibrium disassociation constant (k_d/k_a). k_p and k_dp are rates of phosphorylation and dephosphorylation, respectively. K^B and K^T refer to binary (IFN/IFNAR2) and ternary (IFN/IFNAR2/IFNAR1) complexes, respectively. This figure was adapted from Figure 1 of (24).

Figure 3

Evolution of IFN-I. (A) Simplified evolution of type IFN-I in mammals adapted from Krause and Petska. The most recent common ancestor (MRCA) gave rise to IFNκ and a progenitor for IFNβ. A duplicate of the IFNβ progenitor gave rise to IFNϵ, IFNν (a pseudogene in mammals), and a progenitor for IFNω. The IFNω progenitor gave rise to the remaining subtypes. In simiiforms, IFNαω is deleted and IFNδ is a pseudogene. (B) Evolution of IFN subtypes from simians to homininae showing conserved (blue) and variant (orange) subtypes. Figure adapted from: http://humanorigins.si.edu/evidence/genetics.

Figure 4

IFNB1 and IFNA gene transcription is controlled by IRF3 and IRF7. (A) Promoter region of IFNB1 gene showing the four promoter regulatory domains (PRD), all of which must be engaged for gene transcription. (B) Promoter regions of IFNA1, IFNA16, and IFNA2 aligned with the promoter region of IFNB1 showing the three IRF regulatory modules and their relative sensitivity to IRF3 and IRF7. Differences from IFNA1 promoter are shown in red. The promoter region of IFNA16 is representative of IFNA21 and the variant subtypes (IFNA17, IFNA16, IFNA10, IFNA7, and IFNA4). The IFNA2 promoter region is representative of all IFNA^{− 1/13} conserved subtypes except IFNA21. (C–E) Model of differential regulation of human IFNA genes. Blue and orange shading show evolutionarily conserved and variant IFNα subtypes, respectively, IFNA genes expressed in response to increasing levels of activated IRF3 alone (C), IRF7 alone (D), or IRF3 and IRF7 together (E) as described by Genin et al. (38). (F) Proposed model of IFNα subtype expression in the context of initial activation of IRF3 followed by IRF7 expression (and subsequent activation) in response to a forward feedback loop initiated by IFNβ.

Figure 5

Binding affinities of IFN-I. (A) Equilibrium disassociation constants for the IFN-I. IFNα subtypes are from (63); IFNβ from (64), and IFNϵ, -κ, and -ω from (65). (B) Product of K_D for IFNAR1 and IFNAR2, normalized to IFNα2. Highlighting and bar colors indicate conserved (blue) and variant subtypes (orange).

Figure 6

Amino acid sequence of human IFNα subtypes. IFNα subtypes are shown in order of arrangement on chromosome 9 with evolutionarily conserved and variant subtypes highlighted in blue and pink respectively. Secondary structure and IFNAR1/2 contact residues, labeled 1 and 2 respectively, are shown in the gray and blue highlighted text. Amino acids are shown with IFNα1 as the comparator, showing those that are unique to IFNα1 and otherwise identical among all the IFNα^−1/13 subtypes, or otherwise varies among the other IFNα^1/13 subtypes. * and † indicate cysteine disulfide bonds. Figure modified from (80).