Antiviral actions of Interferons
Interferons (IFNs) are widely expressed cytokines. They modulate antiviral,
antiproliferative and immunomodulatory functions of the cells. The IFN family includes
two main classes of related cytokines: type I IFNs and type II IFN. There are many type I
IFNs, including IFN-alpha (having several subtypes of its
own) and IFN-beta. All type I IFNs bind a common two-subunit
cell-surface receptor known as the type I IFN receptor,or IFN-alpha/beta
receptor. By contrast, there is only one type II IFN,
IFN-gamma, that binds to another receptor,
IFN-gamma receptor, also a
two-subunit protein.
The interaction between IFN receptors and kinases of the Janus activated kinase (JAK)
family is critical for signaling by IFNs. Ligand binding to receptors produces
oligomerization of receptor subunits and results in the activation of cytoplasmic JAKs
that bind to the membrane-proximal domain of specific IFN receptor subunits.
IFN-alpha/beta receptor interacts
with the Janus activated kinases Tyk2 and
JAK1. IFN-gamma
receptor interacts with JAK1
and JAK2. Activation of the JAKs associated with the
IFN-alpha/beta receptor results in tyrosine phosphorylation
of signal transducers and activators of transcription STAT1
and STAT2; this leads to the formation of the complex
between STAT1, STAT2 and
IFN-regulatory factor 9 (IRF9) that is known as
IFN-stimulated gene factor 3 complex (ISGF3). This complex
translocates to the nucleus, binds IFN-stimulated response elements (ISREs) and initiates
gene transcription. Both type I and type II IFNs also induce the formation of
STAT1-STAT1 homodimer. The
latter translocates to the nucleus and binds IFN-gamma-activated site (GAS) elements in
promoter sequences of certain genes, thus initiating their transcription [1].
Transcription factors of the Interferon regulatory factor (IRF) family are also
important regulators in the IFN response. IRF1 binds
directly to the ISRE found in the promoter of IFN-alpha/beta-regulated genes and plays an
important role in the antiviral actions of the IFNs.
IRF3, a key transcriptional activator affected by viral
infection, is constitutively expressed in many cells and tissues, and its activation
leads to the prior induction of the IFN-alpha and
IFN-beta genes. IRF3 is a
subunit of the double-stranded RNA (dsRNA)-activated
transcription factor complex that is directly activated by dsRNA or by virus infection.
Activation of IRF3 results in its cytoplasmic-to-nuclear
translocation and interaction with
p300/CBP co-activators, leading
to the transcriptional activation of the IFN-alpha and
IFN-beta promoters [2].
The following IFN-induced proteins are implicated in the antiviral actions of IFNs in
virus-infected cells: dsRNA-activated protein kinase
(PKR), the 2,5-oligoadenylate
synthetase (OAS) family and
RNaseL nuclease, Adenosine deaminase
(ADAR1), the family of Mx
protein GTPases (including MxA), Indoleamine 2,3-dioxygenase
(INDO), and Inducible Nitric Oxide Synthase
(iNOS) [2].
IFN-inducible PKR is activated by autophosphorylation.
This process is initiated by the double-stranded RNA.
PKR inhibits viral mRNA translation through the
phosphorylation of Eukaryotic translation initiation factor 2, subunit 1
alpha (EIF2S1), a subunit of
the translation initiation factor eIF2 that catalyzes the first regulated step of the
protein synthesis initiation and promotes the binding of the initiator tRNA to 40S
ribosomal subunits [3].
OAS (OAS1, OAS2 and OAS3 synthetases) catalyze the
synthesis of oligoadenylates of the general structure ppp(A2'p)nA (or 2-5A
oligoadenylate). RNaseL, a latent
endoribonuclease, becomes activated by binding 2-5A
oligoadenylate. RNaseL mediates
mRNA degradation. The RNaseL inhibitor
(RLI) is believed to regulate OAS
and RNaseL activity via the formation of a
latent heterodimeric protein complex [4], [5].
RNA-specific adenosine deaminase ADAR1, a
protein inducible by IFN-alpha,
is implicated in the editing of viral RNA transcripts and cellular pre-mRNAs.
ADAR1 catalyzes the covalent modification of RNA substrates
by hydrolytic deamination of adenosine to yield
inosine. The resultant transitions destabilize the
double-stranded RNA helix by disruption base pairing [2], [6], [7].
The Mx protein GTPases (especially cytoplasmic MxA)
appear to target viral nucleocapsids, inhibit RNA synthesis and block viral replication
[1].
Tryptophanyl-tRNA synthetase (WARS) catalyzes the
aminoacylation of tRNA with
(L)-tryptophan, leading to the binding of
(L)-tryptophan to tRNA,
(L)-tryptophan*(tRNA) formation and viral protein synthesis
[8]. Indoleamine 2,3-dioxygenase (INDO) is the
rate-limiting enzyme in the kynurenine (N-formyl-kynurenine)
pathway of (L)-tryptophan metabolism.
INDO-mediated (L)-tryptophan
deprivation protects cells by inhibiting the replication of a variety of pathogens
including viruses [9].
In addition to antiviral effects exerted at the single-cell level that reduce viral
synthesis, IFNs modulate a number of immunoregulatory cell functions. Nitric Oxide
Synthase (iNOS), which is inducible by
IFN-gamma, catalyzes NADPH-dependent oxidation of
(L)-arginine to yield nitric oxide (NO) and citrulline.
NO plays an important role in the host response to infection
and inhibition of virus replication.
The major histocompatibility complex (MHC) MHC class I
and MHC class II molecules present the antigenic peptides
derived from proteolysis of foreign viral protein antigens, to the cytotoxic T cells.
Virus-specific recognition and killing of infected cells are key components of the host
defense to viral infection. Both IFN-alpha/beta and
IFN-gamma induce MHC class I
expression, and IRF1 plays a key role in transcription of
these genes. MHC class II transactivator factor (CIITA) is
the master regulator of MHC class II expression that is
efficiently induced by IFN-gamma. Notably,
CIITA also co-regulates the transcription of
MHC class I. Most cell types do not express basal
CIITA. Expression
of CIITA is inducible by
IFN-gamma [2], [10].
References:
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Mechanisms of type-I- and type-II-interferon-mediated signalling.
Nature reviews. Immunology 2005 May;5(5):375-86
- Samuel CE
Antiviral actions of interferons.
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- Anderson P, Kedersha N
Visibly stressed: the role of eIF2, TIA-1, and stress granules in protein translation.
Cell stress & chaperones 2002 Apr;7(2):213-21
- Bisbal C, Salehzada T, Silhol M, Martinand C, Le Roy F, Lebleu B
The 2-5A/RNase L pathway and inhibition by RNase L inhibitor (RLI).
Methods in molecular biology (Clifton, N.J.) 2001;160:183-98
- Sen GC, Lengyel P
The interferon system. A bird's eye view of its biochemistry.
The Journal of biological chemistry 1992 Mar 15;267(8):5017-20
- George CX, Wagner MV, Samuel CE
Expression of interferon-inducible RNA adenosine deaminase ADAR1 during pathogen infection and mouse embryo development involves tissue-selective promoter utilization and alternative splicing.
The Journal of biological chemistry 2005 Apr 15;280(15):15020-8
- Taylor DR, Puig M, Darnell ME, Mihalik K, Feinstone SM
New antiviral pathway that mediates hepatitis C virus replicon interferon sensitivity through ADAR1.
Journal of virology 2005 May;79(10):6291-8
- Shen N, Guo L, Yang B, Jin Y, Ding J
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- Mellor AL, Munn DH
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