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Interferon alpha-2 is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''IFNA2''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.


Protein family

Human
interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten ...
alpha-2 (IFNα2) is a
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
belonging to the family of type I IFNs. IFNα2 is a protein secreted by cells infected by a
virus A virus is a submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Viruses are ...
and acting on other cells to inhibit
viral infection A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infectious virus particles (virions) attach to and enter susceptible cells. Examples include the common cold, gastroenteritis, COVID-19, t ...
. The first description of IFNs as a cellular agent interfering with
viral replication Viral replication is the formation of biological viruses during the infection process in the target host cells. Viruses must first get into the cell before viral replication can occur. Through the generation of abundant copies of its genome ...
was made by Alick Isaacs and Jean Lindenmann in 1957. The history of this finding was recently reviewed. There are 3 types of IFNs:
Interferon type I The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cy ...
,
Interferon type II Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cell (biology), cell ...
and Interferon type III. The type II IFN, also called IFNγ, is produced by specific cells of the
immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...
. Unlike type I and type III IFNs, IFNγ has only a modest role in directly restricting viral infections. Type I and type III IFNs act similarly. However, the action of type III IFNs, also known as IFNλ, is limited to
epithelial cells Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
while type I IFNs act on all body's cells. Type I IFNs form a family of several proteins: in humans, there are 13 α subtypes, 1 β subtype, 1 ω subtype and other less studied subtypes (κ and ε). IFNα2 was the first subtype to be characterized in the early eighties. As a result, IFNα2 was widely used in basic research to elucidate biological activities, structure and mechanism of action of type I IFNs. IFNα2 was also the first IFN to be produced by the pharmaceutical industry for use as a drug. Thereby, IFNα2 is the best known type I IFN subtype. The properties of IFNα2 are widely shared by the other type I IFNs, although subtle differences exist.


Gene and protein

The
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
encoding IFNα2, the IFNA2 gene, is clustered with all other type I IFN genes on chromosome 9 and as all type I IFN genes, it is devoid of
intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of the cistron .e., gen ...
. The
open reading frame In molecular biology, reading frames are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible reading frames ...
( coding sequence) of IFNA2 codes for a pre-protein of 188
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s with a 23 amino acid
signal peptide A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16–30 amino acids long) present at the ...
allowing secretion of the mature protein. The mature protein is made of 165 amino acids, one less than the other human IFNα subtypes. The
secondary structure Protein secondary structure is the local spatial conformation of the polypeptide backbone excluding the side chains. The two most common Protein structure#Secondary structure, secondary structural elements are alpha helix, alpha helices and beta ...
of IFNα2 consists of five α-helices: A to E, from the
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
to the
C-terminal end The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When ...
. Helices A, B, C and E are organized as a bundle with a long loop between the helices A and B (the A-B loop) and two
disulfide bonds In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In in ...
which connect helix E to the A-B loop and helix C to the N-terminal end. Several variants, or allelic variants, have been identified in the human population. Among them, IFNα2a and IFNα2b are better known by their commercial name, Roferon-A and Intron A, respectively. Upstream of the coding sequence is the promoter region that contains sequences that regulate the transcription of the IFNA2 gene into a
messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...
(mRNA). The amino acid sequences of IFNα2a and IFNα2b differ only at position 23 (lysine in IFNα2a, arginine in IFNα2b).


Synthesis

When a cell is infected by a virus, some components of the virus, mainly viral
nucleic acids Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nucleic a ...
, are recognized by specialized cellular molecules such as
RIG-I RIG-I (retinoic acid-inducible gene I) is a cytosolic pattern recognition receptor (PRR) that can mediate induction of a type-I interferon (IFN1) response. RIG-I is an essential molecule in the innate immune system for recognizing cells that ...
, MDA5 and some
toll-like receptors Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane protein, single-spanning receptor (biochemistry), receptors usually expressed on sentinel cells such as macrophages ...
(TLR). This recognition induces the activation of specific serine
kinases In biochemistry, a kinase () is an enzyme that catalysis, catalyzes the transfer of phosphate groups from High-energy phosphate, high-energy, phosphate-donating molecules to specific Substrate (biochemistry), substrates. This process is known as ...
, enzymes which activate by
phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...
the IFN regulatory factors (IRF), IRF3 and IRF7. IRF3 and IRF7 are themselves
transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...
that translocate into the nucleus and activate the transcription of type I IFNs genes and thereby initiate the process leading to the secretion of IFN by the infected cells. The "danger" signals carried by viruses were the first IFN inducers described but it is now known that non-viral "danger" signals, such as some types of dead cells, can stimulate the synthesis of type I IFNs.


Mechanism of action

Induced IFNα2 is secreted by the infected cells and acts locally as well as systemically on cells expressing a specific
cell surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integra ...
able to bind type I IFNs. The type I IFN receptor ( IFNAR) is composed of two subunits, IFNAR 1 and IFNAR 2, which are expressed by all body's cells. After binding to its receptor, type I IFNs activate multiple cellular factors that transduce the signal from the cell surface into the nucleus. The main signaling pathway activated by type I IFNs consists of a series of events: * phosphorylation and activation of two enzymes of the Janus kinases or JAK family, TYK2 which is associated with IFNAR1 and JAK1 associated to IFNAR2; * phosphorylation by the activated JAK kinases of key transcription factors, namely STAT1 and STAT2, members of the family Signal Transducer and Activator of Transcription (
STAT protein 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, ...
); * phosphorylated STAT1 and STAT2 bind IRF9 forming a complex named "IFN-Stimulated Gene Factor 3" (ISGF3). This complex translocates in the nucleus and initiates the transcription of the IFN-stimulated genes (ISGs). ISGs encode proteins that modulate cellular functions. Following viral infection, many ISGs lead to the inhibition of the viral spread. Several ISGs inhibit viral replication in the infected cells. Other ISGs protect neighbouring uninfected cells from being infected by inhibiting viral entry. Several hundreds of ISGs are known to be activated by type I IFNs and are listed in a searchable database named interferome (http://www.interferome.org/).


Function

The broad spectrum of ISGs explains the wide range of biological activity of type I IFNs. In addition to their antiviral activity, type I IFNs also inhibit the proliferation of cells and regulate the activation of the immune system. Type I IFNs exert potent antitumor activity by several mechanisms such as: * inhibition of the proliferation of cancer cells * activation of the immune system which can eliminate tumor cells * increasing the antitumor activity of other antitumoral agents (
radiotherapy Radiation therapy or radiotherapy (RT, RTx, or XRT) is a treatment using ionizing radiation, generally provided as part of cancer therapy to either kill or control the growth of malignant cells. It is normally delivered by a linear particle ...
,
chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...
, targeted therapies) Type I IFNs can have detrimental effects during viral and non-viral infections (bacterial, parasitic, fungal). This is due in part by the ability of type I IFNs to polarize the immune system towards a specific type of response in order to interfere with virus infections. When improperly regulated, IFN production or IFN-induced signalling can result in
autoimmune diseases An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated that ...
, such as systemic lupus erythematosus.


Clinical significance

If given orally, IFNα2 is degraded by
digestive enzymes Digestive enzymes take part in the chemical process of digestion, which follows the mechanical process of digestion. Food consists of macromolecules of proteins, carbohydrates, and fats that need to be broken down chemically by digestive enzymes ...
and is no longer active. Thus, IFNα2 is mainly administrated by
injection Injection or injected may refer to: Science and technology * Injective function, a mathematical function mapping distinct arguments to distinct values * Injection (medicine), insertion of liquid into the body with a syringe * Injection, in broadca ...
essentially subcutaneous or
intramuscular Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles hav ...
. Once in the blood, IFNα2 is rapidly eliminated by the kidney. Due to the short life of IFNα2 in the organism, several injections per week are required. Peginterferon alpha-2a and Peginterferon alpha-2b (
polyethylene glycol Polyethylene glycol (PEG; ) is a polyether compound derived from petroleum with many applications, from industrial manufacturing to medicine. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular wei ...
linked to IFNα2) are long-lasting IFNα2 formulations, which enable a single injection per week. Recombinant IFNα2 (α2a and α2b) has demonstrated efficiency in the treatment of patients diagnosed with some viral infections (such as chronic viral
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. ...
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 period, people often have mild or no symptoms. Early symptoms can include ...
) or some kinds of cancer (
melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...
,
renal cell carcinoma Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the Proximal tubule, proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cance ...
and various hematological malignancies). Yet, patients on therapy with IFNα2 suffer from adverse effects which often require to reduce or even stop the treatment. These adverse effects include flu-like symptoms such as chills, fever, joint and muscle pain, depression with suicidal ideation, and a reduction in the number of blood cells. Thereby, IFNα2 has been progressively replaced by better tolerated drugs, such as antiviral agents or targeted antitumor therapies. Chronic viral hepatitis C is the main indication for which IFNα2 remains widely used. Nevertheless, there is increasing evidence that endogenous type I IFNs plays a role in the induction of an immune antiviral response and that they can enhance the antitumor activity of chemotherapies, radiotherapies and some targeted therapies. Therefore, an important future goal for scientists is to modify IFNα2 in order to obtain an active molecule to be used in the clinic that does not exert
adverse effects An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complic ...
. Anecdotal evidence suggests interferon alfa 2b is effective antiviral treatment in COVID-19


Notes


References


Further reading

*


External links

* {{Cytokine receptor modulators