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The interferon-α/β receptor (IFNAR) is a virtually ubiquitous membrane receptor which binds endogenous
type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T cell, T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p2 ...
(IFN) cytokines. Endogenous human type I IFNs include many subtypes, such as interferons-α, -β, -ε, -κ, -ω, and -ζ.


Function

Activation of various innate immune signaling pathways (
TLR3 Toll-like receptor 3 (TLR3) also known as CD283 (cluster of differentiation 283) is a protein that in humans is encoded by the ''TLR3'' gene. TLR3 is a member of the toll-like receptor family of pattern recognition receptors of the innate immune ...
,
TLR4 Toll-like receptor 4 is a protein that in humans is encoded by the ''TLR4'' gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an ...
,
TLR7 Toll-like receptor 7, also known as TLR7, is a protein that in humans is encoded by the ''TLR7'' gene. Orthologs are found in mammals and birds. It is a member of the toll-like receptor (TLR) family and detects single stranded RNA. Function T ...
,
TLR8 Toll-like receptor 8 is a protein that in humans is encoded by the ''TLR8'' gene. TLR8 has also been designated as CD288 (cluster of differentiation 288). It is a member of the toll-like receptor (TLR) family. Function TLR8 seems to function d ...
,
TLR9 Toll-like receptor 9 is a protein that in humans is encoded by the ''TLR9'' gene. TLR9 has also been designated as CD289 (cluster of differentiation 289). It is a member of the toll-like receptor (TLR) family. TLR9 is an important receptor expresse ...
, cGAS,
RIG-I RIG-I (retinoic acid-inducible gene I) is a cytosolic pattern recognition receptor (PRR) responsible for the type-1 interferon (IFN1) response. RIG-I is an essential molecule in the innate immune system for recognizing cells that have been infect ...
, MDA-5) leads to the rapid induction of type I IFNs due to their (mostly) intronless gene structure. The regulatory elements upstream of type I IFN genes differ, allowing differential transcription of type I IFNs in response to stimuli. In particular, IFNβ contains a κB regulatory site, whereas IFNα subtypes do not. Production of specific type I IFNs is usually limited to a small number of type I IFN subtypes. Once secreted, type I IFNs signal through IFNAR in a
paracrine Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over ...
and
autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with p ...
manner. IFNAR is a heteromeric cell surface receptor composed of two subunits, referred to as the low affinity subunit,
IFNAR1 Interferon-alpha/beta receptor alpha chain is a protein that in humans is encoded by the ''IFNAR1'' gene. Function The protein encoded by this gene is a type I membrane protein that forms one of the two chains of a receptor for type I interfer ...
, and the high affinity subunit,
IFNAR2 Interferon-alpha/beta receptor beta chain is a protein that in humans is encoded by the ''IFNAR2'' gene. Function The protein encoded by this gene is a type I membrane protein that forms one of the two chains of a receptor for interferons al ...
. Upon binding of type I interferons, IFNAR activates the JAK-STAT signalling pathway, along with
MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
,
PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
, and
Akt Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tran ...
signaling pathways. IFNAR agonism results in transcriptional changes, with the potential to increase or suppress the transcription of over 2000 different genes. For example, type I IFNs induce interferon-stimulated gene ( ISG) expression, classically resulting in a robust anti-viral immune response. Additionally, IFNs largely impact cell health and viability, with effects on
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, autophagy, cell differentiation, and proliferation. The diverse effects of type I IFNs is likely dependent on the cellular and environmental context. Different responses, e.g. antiviral versus antiproliferative responses, to type I IFNs subtypes have been studied and proximal signaling, such as
STAT STAT, Stat. , or stat may refer to: * Stat (system call), a Unix system call that returns file attributes of an inode * ''Stat'' (TV series), an American sitcom that aired in 1991 * Stat (website), a health-oriented news website * STAT protein, a ...
phosphorylation, does not appear to correlate with the outcome. Furthermore, while differential effects manifest after several days of chronic stimulation, changes to receptor structure, orientation, or stoichiometry have not elucidated the cause for differential signaling via different type I IFN subtypes. Current hypotheses for differential signaling include ligand-specific differences to the stability, or lifetime, of the ternary complex, ligand-induced changes to internalization and trafficking of the receptor and currently unappreciated differences to ligand-receptor structure.


Structure

Type I IFN receptor forms a ternary complex, composed of its two subunits IFNAR1 and IFNAR2, and a type I IFN ligand. Ligand binding to either subunit is required for and precedes dimerization and activation of the receptor. Each subunit of IFNAR contains an N-terminal ligand binding domain (with two or four fibronectin type II-like subdomains, for IFNAR2 and IFNAR1, respectively), a transmembrane (TM) domain, and a cytoplasmic domain. Each type I IFN ligand contains a "hotspot", or a sequence of conserved amino acids that are involved in binding to the receptor, specifically the high affinity receptor IFNAR2, which determines the affinity of each ligand for the receptor. Structural analysis of type I IFN receptor with different type I IFN ligand subtypes revealed a similar binding site for the different agonists. Mutagenesis studies of type I IFNs, IFNAR1 and IFNAR2 demonstrated important binding residues, i.e. "hotspots", on the type I IFN subtypes which influenced its ability to bind to IFNAR2. Type I IFN binding to IFNAR1 was less strongly impacted by mutating single amino acids to alanine. Importantly, structural studies have not revealed differences in ternary complex structures with IFNAR and various type I IFN subtypes, despite differences in ligand affinities. The evolutionary conservation of type I IFN subtypes binding the same IFNAR receptor at the same site with differing affinities suggests that type I IFNs are nonredundant and potentially regulate different cellular responses. Efforts to engineer a more potent IFNα2 elicited a cellular response similar to IFNβ, suggesting that the affinity of type I IFNs for IFNAR has an important role in regulating the downstream response.


Subunits

Human IFNAR1 and IFNAR2 genes are located on chromosome 21q22.1.


IFNAR1

IFNAR1 is the low affinity subunit, originally cloned in 1990, and is composed of four fibronectin type II-like (FNII-like) subdomains, termed SD1-4. Type I IFNs bind SD1-3 with a typical binding affinity between 0.5–5μM; IFNα1 and IFNβ are exceptions with binding affinities of 220nM and 100nM, respectively. Type I IFNs have a binding association rate of 5x105M/s with a variable dissociation rate that determines type I IFN subtype affinity for IFNAR1. IFNAR1 cytoplasmic domain associates with
Tyk2 Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the ''TYK2'' gene. Tyk2 was the first member of the JAK family that was described (the other members are JAK1, JAK2, and JAK3). It has been implicated in IFN-α ...
and Tyk2 is required for membrane expression of IFNAR1. In the absence of Tyk2, a cytoplasmic IFNAR1 motif is phosphorylated, inducing receptor internalization. IFNAR1 then localizes to the perinuclear endosomal compartment and is degraded. Tyk2 null cells retain some responsiveness to IFNβ. However, responsiveness to IFNα is ablated, likely due to the reduced IFNAR1 membrane expression. IFNAR1 binding to low affinity ligands, such as IFNα subtypes, has been proposed to be the rate-limiting step in the ternary complex formation. Therefore, if membrane levels of IFNAR1 are too low, the binary IFNα-IFNAR2 complex will be unable to recruit it to induce signaling. This hypothesis is supported by observations that cell lines with low IFNAR1 expression respond to IFNβ but not IFNα.


IFNAR2

IFNAR2 is the high affinity subunit, originally cloned in 1994, composed of two FNII-like subdomains, termed D1 and D2. Type I IFNs bind D1 and D2 with a typical binding affinity between 0.4–5nM; IFNβ binds at a slightly lower affinity (0.1nM). Type I IFNs have a binding association rate of 10−6–10−7M/s with a variable dissociation rate that determines type I IFN subtype affinity for IFNAR2. IFNAR2 is expressed as three isoforms due to alternative splicing, exon skipping, and multiple polyadenylation sites; IFNAR2a (a soluble form lacking the TM domain), IFNAR2b (a soluble form lacking the cytoplasmic domain), and IFNAR2c (the membrane bound, signaling-competent form). The cytoplasmic domain of IFNAR2c associates with
JAK1 JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain (γc) of type I cytokine receptors, to elicit signals from the IL-2 receptor family (e.g. IL-2R, I ...
.


Signaling

Type I IFNs bind to IFNAR1 or IFNAR2, forming a binary complex. The binary complex further recruits the remaining IFNAR subunit, completing the ternary complex and activating downstream JAK/STAT signaling. IFN ligation to IFNAR brings the receptor associated kinases, JAK1 and Tyk2, into close proximity, resulting in kinase transphosphorylation and subsequent phosphorylation of tyrosines on IFNAR1 and IFNAR2. Phosphotyrosine residues on IFNAR1 and IFNAR2 recruit
STAT STAT, Stat. , or stat may refer to: * Stat (system call), a Unix system call that returns file attributes of an inode * ''Stat'' (TV series), an American sitcom that aired in 1991 * Stat (website), a health-oriented news website * STAT protein, a ...
proteins (classically
STAT1 Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the ''STAT1'' gene. It is a member of the STAT protein family. Function All STAT molecules are phosphorylated by receptor associ ...
, STAT2, or
STAT3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respons ...
, although
STAT4 Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family, composed of STAT1, STAT2, STAT3, STAT5A, STAT5B, STAT6. STAT proteins are key activators of gene transcription which bind ...
, STAT5, and
STAT6 Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that belongs to the Signal Transducer and Activator of Transcription (STAT) family of proteins. The proteins of STAT family transmit signals from a receptor com ...
may play a role in certain cell types) via their
SH2 domain The SH2 (Src Homology 2) domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins. SH2 domains allow proteins containing those domains to dock to phosphor ...
s. Once recruited, STAT proteins are phosphorylated by which induces their homo- or heterodimerization. These dimers translocate to the nucleus, binding interferon-stimulated response elements (ISRE) and gamma activating sequences (GAS), promoting gene transcription.


Regulation

Under normal conditions, type I IFN levels are homeostatically regulated to balance the benefits of protection from viral infection with the other cellular effects associated with type I IFN signaling, such as apoptosis, cell cycle arrest, and immune modulation. The stringent regulation of type I IFN signaling suggests the importance of timing and location. Type I IFN signaling is controlled through various mechanisms, including differential expression of signaling components, differential signaling following IFNAR engagement, endocytosis and downregulation of the receptors. and negative feedback mechanisms


Differential expression

Responsiveness to type I IFNs requires the expression of signaling components within a given target cell, including IFNAR and STATs. Expression levels and post-translational modifications to IFNAR and STATs can modify cell responsiveness. Importantly, signaling is impacted by different STAT protein expression levels and activation of STAT heterodimers and STAT homodimers; reducing STAT expression levels alters antiviral, antiproliferative and inflammatory responses to type I IFNs. Conversely, increased expression of STAT1 and IRF9 maintain ISG expression, even in the absence of on-going cytokine receptor signaling, thereby amplifying IFNAR signaling. Because type I IFN signaling modulates proteins involved in protein translation, it can also indirectly alter protein levels of induced genes and proteins involved in pathway signaling. Type I IFN subtypes, ranging from 30–70% homology, all bind the same receptor. Biased agonism has been studied in order to better understand how a single receptor responds differently to multiple cognate ligands, culminating in disparate outcomes.


Endocytosis and downregulation

IFNAR1 and IFNAR2 can be internalized through endocytosis in response to agonism through clathrin-dependent and clathrin-independent mechanisms. IFNAR subunits can be differentially downregulated following IFN stimulation. For example, membrane IFNAR1 is reduced in response to IFNα, but surface levels IFNAR1 and IFNAR2 are downregulated in response to IFNβ binding. In agreement with these observations, IFNAR internalization is often associated with the respective agonist's ability to induce an anti-proliferative effect. IFNAR subunit internalization is also observed under basal conditions, with greater basal turnover of IFNAR1 than IFNAR2. IFNAR1 contains a degron, or a motif for ubiquitination, which allows for its internalization and degradation. Tyk2 may block this degron, preventing its internalization.


= Clathrin-dependent endocytosis

= Following receptor agonism, the C-terminus of IFNAR is phosphorylated, followed by its ubiquitination and internalization. IFNAR surface expression is maintained in the presence of stimulation when the clathrin-dependent endocytosis pathway is inhibited with siRNA knockdown of clathrin or using a small molecule inhibitor of the
GTPase GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...
dynamin Dynamin is a GTPase responsible for endocytosis in the eukaryotic cell. Dynamin is part of the "dynamin superfamily Dynamin Superfamily Protein (DSP) is a protein superfamily includes classical dynamins, GBPs, Mx proteins, OPA1, mitofusins i ...
. Internalization can result in degradation of the receptor, thereby reducing membrane expression, or it can result in recycling of the receptor without an extended impact on membrane receptor levels. However, clathrin-mediated endocytosis may also serve to concentrate the IFNAR receptors and signaling components, thereby amplifying signaling. Electron microscopy experiments show IFNAR receptors concentrated in clathrin-coated pits, and inhibition of clathrin-mediated endocytosis resulted in reduced phosphorylation of JAK1, Tyk2, STATs and reduced STAT nuclear translocation.


Negative feedback mechanisms

Negative regulators of type I IFN signaling, such as
suppressor of cytokine signaling 1 Suppressor of cytokine signaling 1 is a protein that in humans is encoded by the ''SOCS1'' gene. ''SOCS1'' orthologs have been identified in several mammals for which complete genome data are available. Function This gene encodes a member of t ...
(SOCS1) and ubiquitin-specific peptidase 18 (
USP18 Ubiquitin specific peptidase 18 (USP18), also known as UBP43, is a type I interferon receptor repressor and an isopeptidase. In humans, it is encoded by the ''USP18'' gene. USP18 is induced by the immune response to type I and III interferons, ...
), are induced after 4 hours. SOCS1 inhibits type I IFN signaling by inhibiting JAKs and binding phosphorylated Tyk2. USP18 binds to the C terminus of IFNAR2. USP18 may regulate type I IFN signaling by interfering with ternary complex formation, not through its peptidase function. Loss of USP18 results in an inflammatory interferon-mediated CNS disease.


Clinical implications

Type I IFN can provide both beneficial or deleterious effects in a variety of diseases. Type I IFN is thought to be a driver in multiple autoimmune diseases and may have a role in chronic infection. Conversely, type I IFNs are also prescribed as therapeutics in other disease indications. In particular, type I IFN are implicated in the pathogenesis of the following autoimmune diseases:
systemic lupus erythematosus Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
(SLE), Sjogren's syndrome,
systemic sclerosis Systemic scleroderma, or systemic sclerosis, is an autoimmune rheumatic disease characterised by excessive production and accumulation of collagen, called fibrosis, in the skin and internal organs and by injuries to small arteries. There are two m ...
,
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
(RA), and
myositis Myositis is a rare disease that involves inflammation of the muscles. This can present with a variety of symptoms such as skin involvement (i.e., rashes), muscle weakness, and other organ involvement. Systemic symptoms such as weight loss, fatigue ...
. Increased levels of intracerebral IFNα are also thought to play a detrimental role in
Aicardi–Goutières syndrome Aicardi–Goutières syndrome (AGS), which is completely distinct from the similarly named Aicardi syndrome, is a rare, usually early onset childhood, inflammatory disorder most typically affecting the brain and the skin (neurodevelopmental disord ...
(AGS),
HIV-associated dementia HIV-associated neurocognitive disorders (HAND) are neurological disorders associated with HIV infection and AIDS. It is a syndrome of progressive deterioration of memory, cognition, behavior, and motor function in HIV-infected individuals during ...
and CNS lupus. While type I IFNs are one of the classical cytokines required for an effect antiviral response, higher type I IFN levels are associated with worsening disease in bacterial infections, such as
tuberculosis Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in ...
and
lepromatous leprosy Lepromatous leprosy is a form of leprosy characterized by pale macules in the skin. It results from the failure of Th1 cell activation which is necessary to eradicate the mycobacteria (Th1 response is required to activate macrophages that engulf ...
. Type I IFN is also being investigated for a potential role in neurodegeneration; loss of IFNAR expression prolonged survival in murine models of
amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
(ALS). IFNα has also been used in the clinic for the treatment of type I IFN responsive hematological malignancies, such as
chronic myelogenous leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulat ...
(CML),
multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...
, and
hairy cell leukemia Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes. It is usually classified as a subtype of chronic lymphocytic leukemia (CLL). Hairy cell leukemia makes up about 2% of all le ...
. Importantly, type I IFN-resistant cancers have been shown to have low or absent IFNAR expression. Additionally, IFNα was also given therapeutically for the treatment of some potentially chronic viral infections, such as
hepatitis B Hepatitis B is an infectious disease caused by the ''Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. Fo ...
and
hepatitis C Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, a ...
. Paradoxically, IFNβ was first-line treatment for the central autoimmune disease,
multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
(MS), although the mechanism of action for IFNβ in MS has not been definitively demonstrated.


References


External links

* {{DEFAULTSORT:Interferon-alpha beta receptor Type II cytokine receptors