RIG-I (retinoic acid-inducible gene I) is a

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

pattern recognition receptor Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of ...

(PRR) responsible for the type-1 interferon (IFN1) response. RIG-I is an essential molecule in the

innate immune system The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...

for recognizing cells that have been infected with a virus. These viruses can include

West Nile virus West Nile virus (WNV) is a single-stranded RNA virus that causes West Nile fever. It is a member of the family '' Flaviviridae'', from the genus '' Flavivirus'', which also contains the Zika virus, dengue virus, and yellow fever virus. The v ...

, Japanese Encephalitis virus, influenza A, Sendai virus, flavivirus, and

coronavirus Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans and birds, they cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include some cases of the co ...

es. RIG-I is structurally considered a helical ATP-dependent DExD/H box

RNA helicase Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separ ...

, that recognizes short viral double-stranded RNA (dsRNA) in the cytosol during a viral infection or other irregular RNAs (i.e., non-coding RNAs). Once activated by the dsRNA, the N-terminus caspase activation and recruitment domains (CARDs) migrate and bind with CARDs attached to mitochondrial antiviral signaling protein ( MAVS) to activate the signaling pathway for IFN1. IFN1s have three main functions: to limit the virus from spreading to nearby cells, promote an innate immune response, including inflammatory responses, and help activate the

adaptive immune system The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...

. Other studies have shown that in different microenvironments, such as in cancerous cells, RIG-I has more functions other than viral recognition. RIG-I orthologs are found in mammals, geese, ducks, some fish, and some reptiles. RIG-I is in most cells, including various innate immune system cells, and is usually in an inactive state.

Knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

that have been designed to have a deleted or non-functioning RIG-I gene are not healthy and typically die embryonically. If they survive, the mice have serious developmental dysfunction. The stimulator of interferon genes

STING Sting may refer to: * Stinger or sting, a structure of an animal to inject venom, or the injury produced by a stinger * Irritating hairs or prickles of a stinging plant, or the plant itself Fictional characters and entities * Sting (Middle-earth ...

antagonizes RIG-1 by binding its N-terminus, probably as to avoid overactivation of RIG-1 signaling and the associated

autoimmunity In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...

Structure

RIG-I is encoded by the ''DDX58''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

in humans. RIG-I is a helical ATP-dependent DExD/H box

with a repressor domain (RD) on the

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal 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 the protein i ...

that binds to the target RNA. Included on the

N-terminus 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 ami ...

are two caspase activation and recruitment domains (CARDs) that are important for interactions with mitochondrial antiviral signaling protein (MAVS). RIG-I is a member of the RIG-I like receptors (RLRs) that also includes Melanoma Differentiation-Associated protein 5 (MDA5) and Laboratory of genetics physiology 2 (

LGP2 Probable ATP-dependent RNA helicase DHX58 also known as RIG-I-like receptor 3 (RLR-3) or RIG-I-like receptor LGP2 (RLR) is a RIG-I-like receptor dsRNA helicase enzyme that in humans is encoded by the ''DHX58'' gene. The protein encoded by the ge ...

). RIG-I and MDA5 are both involved in activating MAVS and triggering an antiviral response.

Functions

As a Pattern Recognition Receptor

Pattern Recognition Receptors

Pattern Recognition Receptors Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells o ...

(PRRs) are a part of the innate immune system used for recognizing invaders. In a viral infection, a

virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsk ...

enters a cell, and it takes over the cell's machinery to self replicate. Once a virus has begun replication, the infected cell is no longer useful and potentially harmful to its host, and the host's immune system must be notified. RIG-I functions as a pattern recognition receptor and PRR's are the molecules that start the notification process. PRRs recognize specific Pathogen-Associated Molecular Patterns (PAMP). Once the PAMP is recognized, it can then lead to a signaling cascade producing an inflammatory response or an interferon response. PRRs are located in many different cell types, however most notably active in the

cells. In addition, they are located in many different parts of those cells, such as the cell membrane, endosomal membrane, and in the cytosol, to provide the most protection against many types of invaders (i.e., extracellular and intracellular microbes).

RIG-I PAMPs

RIG-I is located in the cytoplasm where its function is to recognize its PAMP, which are ideally short (<300 base pairs) dsRNA with a 5′ triphosphate (5′ ppp). However, it has been noted that while not ideal, and response is weakened, RIG-I can recognize 5′ diphosphate (5′pp). This ability is important as many viruses have evolved to evade RIG-I, so having the dual

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elect ...

opens up more doors for recognition. An example of viruses evolving to evade RIG-I is in the case of certain retroviruses, such as HIV-1, encode a protease that directs RIG-I to the lysosome for degradation, and thereby evade RIG-I mediated signaling. The dsRNA can come from single-stranded RNA (ssRNA) viruses or from dsRNA viruses. The ssRNA viruses are not typically recognized as ssRNA, but through intermittent replication products in the form of dsRNA. RIG-I is also able to detect non-self 5′-triphosphorylated dsRNA transcribed from AT-rich dsDNA by DNA-dependent RNA polymerase III (Pol III). It is important to note, however, that the ligands of RIG-I are still being investigated and are controversial. Also notable, is that RIG-I can work together with MDA5 against viruses that RIG-I itself may not create a significant enough response. In addition, for many viruses, effective RIG-I-mediated antiviral responses are dependent on functionally active LGP2. Cells are synthesizing multiple types of RNA at all times, so it is important that RIG-I is not going to bind to those RNAs. Native RNA from inside the cell contains an N₁ 2'O-Methyl self RNA marker that deters RIG-I from binding.

Type-1 Interferon Pathway

RIG-I is a signaling molecule and is usually in a condensed resting state until it is activated. Once RIG-1 is bound to its PAMP, molecules such as PACT and zinc antiviral protein short isoform (ZAPs), help keep RIG-I in an activated state which then keeps the caspase activation and recruitment domains (CARDs) ready for binding. The molecule will migrate to the mitochondrial antiviral signaling protein ( MAVS) CARD domain and bind. RIG-I CARD interactions have their own regulatory system. Although RIG-I expresses a CARD at all times, it must be activated by the ligand before it will allow both CARDs to interact with the MAVS CARD. This interaction will start the pathway to making

proinflammatory cytokines An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include in ...

and type-1 Interferon (IFN1; IFNα and IFNβ), which create an antiviral environment. Once the IFN1s leave the cell, they can bind to IFN1 receptors on the cell surface from which they came from, or other cells close by. This will upregulate the production of more IFN1s, boosting an antiviral environment. IFN1 also activates the

JAK-STAT The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumour formation. The pathway communicates information from chemical signals ou ...

pathway, leading to the production of IFN-stimulated genes (ISGs).

In Cancer Cells

Usually, RIG-I recognizes foreign RNA. However, it can sometimes recognize "self" RNAs. RIG-I has been shown to enable

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...

cells (BrCa) to resist treatments and grow because of an IFN response to noncoding RNA. In contrast, RIG-I in other types of cancer, such as acute myeloid leukemia and

hepatocellular carcinoma Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. It occurs in t ...

, can act as a tumor suppressor. If cancer causing viruses infect a cell, however, RIG-I can lead to cell death. Cell death can occur via

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 in ...

via the caspase-3 pathway, or through IFN-dependent T cells and

natural killer cell Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and repre ...