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60-427: 23586 230073 ENSG00000107201 ENSMUSG00000040296 O95786 Q6Q899 NM_014314 NM_172689 NP_055129 NP_766277 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 have been infected with

120-458: A 5' 7-methyl guanosine (m7G) cap (cap-0), but not RNA with a 5' m7G cap having a ribose 2′-O-methyl modification (cap-1). These are often generated during a viral infection but can also be host-derived. 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

180-501: A molecular mass of less than 300  Da . This mixture of small molecules is extraordinarily complex, as the variety of molecules that are involved in metabolism (the metabolites ) is immense. For example, up to 200,000 different small molecules might be made in plants, although not all these will be present in the same species, or in a single cell. Estimates of the number of metabolites in single cells such as E. coli and baker's yeast predict that under 1,000 are made. Most of

240-416: 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

300-513: A cell, however, RIG-I can lead to cell death. Cell death can occur via apoptosis via the caspase-3 pathway, or through IFN-dependent T cells and natural killer cells . In 2000, RIG-I was named by researchers from the Shanghai Institute of Hematology who identified novel genes that respond to all- trans retinoic acid (ATRA) in leukemia cells. RIG-I and the other genes were assigned the temporary name of RIG (retinoic acid–induced gene) in

360-535: A class of microbes, but not present in the host. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals. This allows the innate immune system to recognize pathogens and thus, protect the host from infection. Although the term "PAMP" is relatively new, the concept that molecules derived from microbes must be detected by receptors from multicellular organisms has been held for many decades, and references to an "endotoxin receptor" are found in much of

420-409: A large central cavity that is isolated from the remainder of the cytosol. One example of such an enclosed compartment is the proteasome . Here, a set of subunits form a hollow barrel containing proteases that degrade cytosolic proteins. Since these would be damaging if they mixed freely with the remainder of the cytosol, the barrel is capped by a set of regulatory proteins that recognize proteins with

480-585: A low concentration of sodium ions. This difference in ion concentrations is critical for osmoregulation , since if the ion levels were the same inside a cell as outside, water would enter constantly by osmosis - since the levels of macromolecules inside cells are higher than their levels outside. Instead, sodium ions are expelled and potassium ions taken up by the Na⁺/K⁺-ATPase , potassium ions then flow down their concentration gradient through potassium-selection ion channels, this loss of positive charge creates

540-421: A much denser meshwork of actin fibres than the remainder of the cytosol. These microdomains could influence the distribution of large structures such as ribosomes and organelles within the cytosol by excluding them from some areas and concentrating them in others. The cytosol is the site of multiple cell processes. Examples of these processes include signal transduction from the cell membrane to sites within

600-429: A multicellular host. The term "PAMP" has been criticized on the grounds that most microbes, not only pathogens, express the molecules detected; the term microbe-associated molecular pattern (MAMP), has therefore been proposed. A virulence signal capable of binding to a pathogen receptor, in combination with a MAMP, has been proposed as one way to constitute a (pathogen-specific) PAMP. Plant immunology frequently treats

660-537: A negative membrane potential . To balance this potential difference , negative chloride ions also exit the cell, through selective chloride channels. The loss of sodium and chloride ions compensates for the osmotic effect of the higher concentration of organic molecules inside the cell. Cells can deal with even larger osmotic changes by accumulating osmoprotectants such as betaines or trehalose in their cytosol. Some of these molecules can allow cells to survive being completely dried out and allow an organism to enter

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720-457: A phenol soluble factor from Staphylococcus epidermidis , and a component of yeast walls called zymosan , are all recognized by a heterodimer of TLR2 and TLR1 or TLR6. However, LTAs result in a weaker pro-inflammatory response compared to lipopeptides, as they are only recognized by TLR2 instead of the heterodimer. First introduced by Charles Janeway in 1989, PAMP was used to describe microbial components that would be considered foreign in

780-439: A protein, its N- and C-terminal ends are highly conserved, due to its necessity for function of flagella. Nucleic acid variants normally associated with viruses , such as double-stranded RNA ( dsRNA ), are recognized by TLR3 and unmethylated CpG motifs are recognized by TLR9 . The CpG motifs must be internalized in order to be recognized by TLR9. Viral glycoproteins, as seen in the viral-envelope, as well as fungal PAMPS on

840-416: A set of proteins with similar functions, such as enzymes that carry out several steps in the same metabolic pathway. This organization can allow substrate channeling , which is when the product of one enzyme is passed directly to the next enzyme in a pathway without being released into solution. Channeling can make a pathway more rapid and efficient than it would be if the enzymes were randomly distributed in

900-677: A signal directing them for degradation (a ubiquitin tag) and feed them into the proteolytic cavity. Another large class of protein compartments are bacterial microcompartments , which are made of a protein shell that encapsulates various enzymes. These compartments are typically about 100–200 nanometres across and made of interlocking proteins. A well-understood example is the carboxysome , which contains enzymes involved in carbon fixation such as RuBisCO . Non-membrane bound organelles can form as biomolecular condensates , which arise by clustering, oligomerisation , or polymerisation of macromolecules to drive colloidal phase separation of

960-462: A state of suspended animation called cryptobiosis . In this state the cytosol and osmoprotectants become a glass-like solid that helps stabilize proteins and cell membranes from the damaging effects of desiccation. The low concentration of calcium in the cytosol allows calcium ions to function as a second messenger in calcium signaling . Here, a signal such as a hormone or an action potential opens calcium channel so that calcium floods into

1020-403: A virus. These viruses can include West Nile virus , Japanese Encephalitis virus , influenza A , Sendai virus , flavivirus , and coronaviruses . RIG-I is an ATP-dependent DExD/H box RNA helicase that is activated by immunostimulatory RNAs from viruses as well as RNAs of other origins. RIG-I recognizes short double-stranded RNA (dsRNA) in the cytosol with a 5' tri- or di-phosphate end or

1080-461: 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 ). RIG-I and MDA5 are both involved in activating MAVS and triggering an antiviral response. Pattern Recognition Receptors (PRRs) are a part of the innate immune system used for recognizing invaders. In a viral infection, a virus enters

1140-466: Is extremely high, and approaches 200 mg/ml, occupying about 20–30% of the volume of the cytosol. However, measuring precisely how much protein is dissolved in cytosol in intact cells is difficult, since some proteins appear to be weakly associated with membranes or organelles in whole cells and are released into solution upon cell lysis . Indeed, in experiments where the plasma membrane of cells were carefully disrupted using saponin , without damaging

1200-428: Is important that RIG-I is not going to bind to those RNAs. Native RNA from inside the cell contains an N 1 2'O-Methyl self RNA marker that deters RIG-I from binding. RIG-I is a signaling molecule and is usually in a condensed resting state until it is activated. Once RIG-I 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

1260-428: 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

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1320-450: Is in most cells, including various innate immune system cells, and is usually in an inactive state. Knockout mice 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 antagonizes RIG-I by binding its N-terminus, probably as to avoid overactivation of RIG-I signaling and

1380-524: 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

1440-456: 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 opens up more doors for recognition. An example of viruses evolving to evade RIG-I

1500-443: 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 mitochondrion into many compartments. In the eukaryotic cell , the cytosol is surrounded by the cell membrane and is part of the cytoplasm , which also comprises the mitochondria, plastids , and other organelles (but not their internal fluids and structures);

1560-451: Is that about 5% of this water is strongly bound in by solutes or macromolecules as water of solvation , while the majority has the same structure as pure water. This water of solvation is not active in osmosis and may have different solvent properties, so that some dissolved molecules are excluded, while others become concentrated. However, others argue that the effects of the high concentrations of macromolecules in cells extend throughout

1620-510: Is when the effective concentration of other macromolecules is increased, since they have less volume to move in. This crowding effect can produce large changes in both the rates and the position of chemical equilibrium of reactions in the cytosol. It is particularly important in its ability to alter dissociation constants by favoring the association of macromolecules, such as when multiple proteins come together to form protein complexes , or when DNA-binding proteins bind to their targets in

1680-464: 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

1740-451: The cell nucleus is separate. The cytosol is thus a liquid matrix around the organelles. In prokaryotes , most of the chemical reactions of metabolism take place in the cytosol, while a few take place in membranes or in the periplasmic space . In eukaryotes, while many metabolic pathways still occur in the cytosol, others take place within organelles. The cytosol is a complex mixture of substances dissolved in water. Although water forms

1800-422: The genome . Although the components of the cytosol are not separated into regions by cell membranes, these components do not always mix randomly and several levels of organization can localize specific molecules to defined sites within the cytosol. Although small molecules diffuse rapidly in the cytosol, concentration gradients can still be produced within this compartment. A well-studied example of these are

1860-553: The "calcium sparks" that are produced for a short period in the region around an open calcium channel . These are about 2  micrometres in diameter and last for only a few milliseconds , although several sparks can merge to form larger gradients, called "calcium waves". Concentration gradients of other small molecules, such as oxygen and adenosine triphosphate may be produced in cells around clusters of mitochondria , although these are less well understood. Proteins can associate to form protein complexes , these often contain

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1920-541: 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 innate immune system 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

1980-513: The TLR4-MD2 complex. Microbes have two main strategies in which they try to avoid the immune system, either by masking lipid A or directing their LPS towards an immunomodulatory receptor. Peptidoglycan (PG) is also found within the membrane walls of gram-negative bacteria and is recognized by TLR2, which is usually in a heterodimer of with TLR1 or TLR6 . Lipoteichoic acid (LTA) from gram-positive bacteria , bacterial lipoproteins (sBLP),

2040-560: The associated autoimmunity . RIG-I is encoded by the DDX58 gene in humans. RIG-I is a helical ATP-dependent DExD/H box RNA helicase with a repressor domain (RD) on the C-terminus that binds to the target RNA. Included on the N-terminus are two caspase activation and recruitment domains (CARDs) that are important for interactions with mitochondrial antiviral signaling protein (MAVS). RIG-I

2100-427: The cell surface or fungi are recognized by TLR2 and TLR4 . Bacterial lipopolysaccharides (LPSs), also known as endotoxins , are found on the cell membranes of gram-negative bacteria , are considered to be the prototypical class of PAMPs. The lipid portion of LPS, lipid A, contains a diglycolamine backbone with multiple acyl chains. This is the conserved structural motif that is recognized by TLR4, particularly

2160-418: The cell, such as the cell nucleus , or organelles. This compartment is also the site of many of the processes of cytokinesis , after the breakdown of the nuclear membrane in mitosis . Another major function of cytosol is to transport metabolites from their site of production to where they are used. This is relatively simple for water-soluble molecules, such as amino acids, which can diffuse rapidly through

2220-443: The cytoplasm or nucleus. Although the cytoskeleton is not part of the cytosol, the presence of this network of filaments restricts the diffusion of large particles in the cell. For example, in several studies tracer particles larger than about 25  nanometres (about the size of a ribosome ) were excluded from parts of the cytosol around the edges of the cell and next to the nucleus. These "excluding compartments" may contain

2280-451: The cytoplasm that is contained within organelles. Due to the possibility of confusion between the use of the word "cytosol" to refer to both extracts of cells and the soluble part of the cytoplasm in intact cells, the phrase "aqueous cytoplasm" has been used to describe the liquid contents of the cytoplasm of living cells. Prior to this, other terms, including hyaloplasm , were used for the cell fluid, not always synonymously, as its nature

2340-410: The cytoskeleton by motor proteins . The cytosol is the site of most metabolism in prokaryotes, and a large proportion of the metabolism of eukaryotes. For instance, in mammals about half of the proteins in the cell are localized to the cytosol. The most complete data are available in yeast, where metabolic reconstructions indicate that the majority of both metabolic processes and metabolites occur in

2400-504: The cytosol and that water in cells behaves very differently from the water in dilute solutions. These ideas include the proposal that cells contain zones of low and high-density water, which could have widespread effects on the structures and functions of the other parts of the cell. However, the use of advanced nuclear magnetic resonance methods to directly measure the mobility of water in living cells contradicts this idea, as it suggests that 85% of cell water acts like that pure water, while

2460-566: The cytosol contains the cell's genome , within a structure known as a nucleoid . This is an irregular mass of DNA and associated proteins that control the transcription and replication of the bacterial chromosome and plasmids . In eukaryotes the genome is held within the cell nucleus , which is separated from the cytosol by nuclear pores that block the free diffusion of any molecule larger than about 10  nanometres in diameter. This high concentration of macromolecules in cytosol causes an effect called macromolecular crowding , which

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2520-433: The cytosol is water , which makes up about 70% of the total volume of a typical cell. The pH of the intracellular fluid is 7.4. while human cytosolic pH ranges between 7.0 and 7.4, and is usually higher if a cell is growing. The viscosity of cytoplasm is roughly the same as pure water, although diffusion of small molecules through this liquid is about fourfold slower than in pure water, due mostly to collisions with

2580-412: The cytosol, and can also prevent the release of unstable reaction intermediates. Although a wide variety of metabolic pathways involve enzymes that are tightly bound to each other, others may involve more loosely associated complexes that are very difficult to study outside the cell. Consequently, the importance of these complexes for metabolism in general remains unclear. Some protein complexes contain

2640-407: The cytosol. However, hydrophobic molecules, such as fatty acids or sterols , can be transported through the cytosol by specific binding proteins, which shuttle these molecules between cell membranes. Molecules taken into the cell by endocytosis or on their way to be secreted can also be transported through the cytosol inside vesicles , which are small spheres of lipids that are moved along

2700-498: The cytosol. Major metabolic pathways that occur in the cytosol in animals are protein biosynthesis , the pentose phosphate pathway , glycolysis and gluconeogenesis . The localization of pathways can be different in other organisms, for instance fatty acid synthesis occurs in chloroplasts in plants and in apicoplasts in apicomplexa . Pathogen-associated molecular pattern Pathogen-associated molecular patterns ( PAMPs ) are small molecular motifs conserved within

2760-407: The cytosol. This sudden increase in cytosolic calcium activates other signalling molecules, such as calmodulin and protein kinase C . Other ions such as chloride and potassium may also have signaling functions in the cytosol, but these are not well understood. Protein molecules that do not bind to cell membranes or the cytoskeleton are dissolved in the cytosol. The amount of protein in cells

2820-550: The format of RIG-A, RIG-B etc by the group, however they performed no additional characterization on RIG-I. Note: RARRES3 (Gene ID: 5920) and DDX58 (Gene ID: 23586) share the RIG1/RIG-1 alias in common. RIG1 is a widely used alternative name for DExD/H-box helicase 58 (DDX58), which can be confused with the retinoic acid receptor responder 3 (RARRES3) gene, since they share the same alias. [22 Jan 2019] Cytosol The cytosol , also known as cytoplasmic matrix or groundplasm ,

2880-585: The large majority of the cytosol, its structure and properties within cells is not well understood. The concentrations of ions such as sodium and potassium in the cytosol are different to those in the extracellular fluid ; these differences in ion levels are important in processes such as osmoregulation , cell signaling , and the generation of action potentials in excitable cells such as endocrine, nerve and muscle cells. The cytosol also contains large amounts of macromolecules , which can alter how molecules behave, through macromolecular crowding . Although it

2940-399: The large numbers of macromolecules in the cytosol. Studies in the brine shrimp have examined how water affects cell functions; these saw that a 20% reduction in the amount of water in a cell inhibits metabolism, with metabolism decreasing progressively as the cell dries out and all metabolic activity halting when the water level reaches 70% below normal. Although water is vital for life,

3000-462: The older literature. The recognition of PAMPs by the PRRs triggers activation of several signaling cascades in the host immune cells like the stimulation of interferons (IFNs) or other cytokines. A vast array of different types of molecules can serve as PAMPs, including glycans and glycoconjugates . Flagellin is also another PAMP that is recognized via the constant domain, D1 by TLR5 . Despite being

3060-407: The other cell membranes, only about one quarter of cell protein was released. These cells were also able to synthesize proteins if given ATP and amino acids, implying that many of the enzymes in cytosol are bound to the cytoskeleton. However, the idea that the majority of the proteins in cells are tightly bound in a network called the microtrabecular lattice is now seen as unlikely. In prokaryotes

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3120-510: The pathway to making proinflammatory cytokines 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 pathway, leading to

3180-445: The production of IFN-stimulated genes (ISGs). Usually, RIG-I recognizes foreign RNA. However, it can sometimes recognize "self" RNAs. RIG-I has been shown to enable breast cancer 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 , can act as a tumor suppressor. If cancer causing viruses infect

3240-421: The remainder is less mobile and probably bound to macromolecules. The concentrations of the other ions in cytosol are quite different from those in extracellular fluid and the cytosol also contains much higher amounts of charged macromolecules such as proteins and nucleic acids than the outside of the cell structure. In contrast to extracellular fluid, cytosol has a high concentration of potassium ions and

3300-473: The signaling pathway for IFN1. Type-I IFNs 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 . 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

3360-449: The structure of this water in the cytosol is not well understood, mostly because methods such as nuclear magnetic resonance spectroscopy only give information on the average structure of water, and cannot measure local variations at the microscopic scale. Even the structure of pure water is poorly understood, due to the ability of water to form structures such as water clusters through hydrogen bonds . The classic view of water in cells

3420-409: The terms "PAMP" and "MAMP" interchangeably, considering their recognition to be the first step in plant immunity, PTI (PAMP-triggered immunity), a relatively weak immune response that occurs when the host plant does not also recognize pathogenic effectors that damage it or modulate its immune response. Mycobacteria are intracellular bacteria which survive in host macrophages . The mycobacterial wall

3480-454: Was first introduced in 1965 by H. A. Lardy, and initially referred to the liquid that was produced by breaking cells apart and pelleting all the insoluble components by ultracentrifugation . Such a soluble cell extract is not identical to the soluble part of the cell cytoplasm and is usually called a cytoplasmic fraction. The term cytosol is now used to refer to the liquid phase of the cytoplasm in an intact cell. This excludes any part of

3540-427: Was not well understood (see protoplasm ). The proportion of cell volume that is cytosol varies: for example while this compartment forms the bulk of cell structure in bacteria , in plant cells the main compartment is the large central vacuole . The cytosol consists mostly of water, dissolved ions, small molecules, and large water-soluble molecules (such as proteins). The majority of these non-protein molecules have

3600-401: Was once thought to be a simple solution of molecules, the cytosol has multiple levels of organization. These include concentration gradients of small molecules such as calcium , large complexes of enzymes that act together and take part in metabolic pathways , and protein complexes such as proteasomes and carboxysomes that enclose and separate parts of the cytosol. The term "cytosol"

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