TRIM5-alpha
Encyclopedia
Tripartite motif-containing protein 5 also known as RING finger protein 88 is a protein
that in humans is encoded by the TRIM5 gene
. The alpha isoform of this protein, TRIM5α, is a retrovirus
restriction factor, which mediates species-specific, early block to retrovirus infection.
TRIM5α is composed of 493 amino acids that is found in the cells
of most primates. TRIM5α is an intrinsic immune factor important in the innate immune defense
against retroviruses, along with the APOBEC
family of proteins, tetherin
and TRIM22
.
(TRIM stands for TRIpartite Motif); this family was first identified by Reddy in 1992 as the proteins that contain a RING finger
zinc binding domain, a B-box zinc binding domain, followed by a coiled-coil region
. TRIM5α bears the C-terminal PRY-SPRY or B30.2 domain in addition to the other domains.
-dependent degradation.
The involvement of other cellular proteins in the inhibition mediated by TRIM5α is suspected but as yet not demonstrated. However, Cyclophilin
A is important for the inhibition of HIV-1 by TRIM5α in Old World monkey species.
The "specificity" of restriction, that is, whether a given retrovirus can be targeted by TRIM5α, is entirely determined by the amino acid
sequence of the C-terminal domain of the protein, called the B30.2/PRY-SPRY domain. Amino acid 332, which occurs within this domain, seems to play a critical role in determining the specificity of retrovirus restriction.
TRIM5α may have played a critical role in the human immune defense system about 4 million years ago, when the retrovirus PtERV1
was infecting chimpanzees. While no trace of PtERV1 has yet been found in the human genome, about 130 traces of PtERV1 DNA have been found in the genome of modern chimpanzees. After recreating part of the PtERV1 retrovirus, it was reported that TRIM5α prevents the virus from entering human cells in vitro. While this cellular defense mechanism may have been very useful 4 million years ago when facing a PtERV1 epidemic
, it has the side effect of leaving cells more susceptible to attack by the HIV-1 retrovirus. Recently, doubt has been cast over these conclusions. By using a PtERV1 capsid, which produces higher titer virus-like particles, Perez-Caballero et al. reported that PtERV1 is not restricted by either human or chimpanzee TRIM5α.
s cannot be infected with HIV-1, the virus that causes AIDS
in human
s; they can be infected, however, with SIV
, a related virus. TRIM5α was isolated as a rhesus macaque
protein responsible for blocking infection by HIV-1.
The human version of TRIM5α does not target HIV-1, but can inhibit strains of the murine leukemia virus
(MLV) as well as equine infectious anemia virus (EIAV).
Prior to the discovery of TRIM5α as an antiviral protein, the inhibition phenotype
had been described and coined Ref1 (in human cells) and Lv1 (in monkey cells). This terminology is now largely abandoned.
A related protein, named TRIMCyp (or TRIM5-CypA), was isolated in owl monkeys, a species of New World monkeys, and shown to potently inhibit infection by HIV-1. A similar protein has arisen independently in Old World monkeys and has been identified in several species of macaque.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the TRIM5 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. The alpha isoform of this protein, TRIM5α, is a retrovirus
Retrovirus
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...
restriction factor, which mediates species-specific, early block to retrovirus infection.
TRIM5α is composed of 493 amino acids that is found in the cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
of most primates. TRIM5α is an intrinsic immune factor important in the innate immune defense
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...
against retroviruses, along with the APOBEC
APOBEC
300px|thumb|upright|alt = Colored dice with checkered background|Example of a member of the APOBEC family, APOBEC-2. A cytidine deaminase from Homo Sapiens....
family of proteins, tetherin
Tetherin
Tetherin also known as bone marrow stromal antigen 2 is a protein that in humans is encoded by the BST2 gene. In addition tetherin has been designated as CD317 .- Function :...
and TRIM22
TRIM22
Tripartite motif-containing 22, also known as TRIM22, is a protein which in humans is encoded by the TRIM22 gene.- Function :The protein encoded by this gene is a member of the tripartite motif family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2,...
.
Structure
TRIM5α belongs to the TRIM protein familyTripartite motif family
-Function:Many TRIM proteins are induced by interferons, which are important component of resistance to pathogens and several TRIM proteins are known to be required for the restriction of infection by lentiviruses...
(TRIM stands for TRIpartite Motif); this family was first identified by Reddy in 1992 as the proteins that contain a RING finger
RING finger domain
In molecular biology, a RING finger domain is a protein structural domain of zinc finger type which contains a Cys3HisCys4 amino acid motif which binds two zinc cations. This protein domain contains from 40 to 60 amino acids...
zinc binding domain, a B-box zinc binding domain, followed by a coiled-coil region
Coiled coil
A coiled coil is a structural motif in proteins, in which 2-7 alpha-helices are coiled together like the strands of a rope . Many coiled coil type proteins are involved in important biological functions such as the regulation of gene expression e.g. transcription factors...
. TRIM5α bears the C-terminal PRY-SPRY or B30.2 domain in addition to the other domains.
Function
When a retrovirus enters a host cell’s cytoplasm, it undergoes processes such as capsid uncoating and reverse transcription. TRIM5 present in the cytoplasm recognizes motifs within the capsid proteins and interferes with the uncoating process, therefore preventing successful reverse transcription and transport to the nucleus of the viral genome. The exact mechanism of action has not been shown conclusively, but capsid protein from restricted viruses is removed by proteasomeProteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
-dependent degradation.
The involvement of other cellular proteins in the inhibition mediated by TRIM5α is suspected but as yet not demonstrated. However, Cyclophilin
Cyclophilin
Cyclophilins are a family of proteins from vertebrates and other organisms that bind to cyclosporine, an immunosuppressant which is usually used to suppress rejection after internal organ transplants...
A is important for the inhibition of HIV-1 by TRIM5α in Old World monkey species.
The "specificity" of restriction, that is, whether a given retrovirus can be targeted by TRIM5α, is entirely determined by the amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence of the C-terminal domain of the protein, called the B30.2/PRY-SPRY domain. Amino acid 332, which occurs within this domain, seems to play a critical role in determining the specificity of retrovirus restriction.
TRIM5α may have played a critical role in the human immune defense system about 4 million years ago, when the retrovirus PtERV1
PtERV1
PtERV1 or Pan troglodytes Endogenous Retrovirus-1 is a retrovirus that putatively infected chimpanzees about 4 million years ago, and may have been involved in the process of speciation, making the chimpanzee and human lines diverge....
was infecting chimpanzees. While no trace of PtERV1 has yet been found in the human genome, about 130 traces of PtERV1 DNA have been found in the genome of modern chimpanzees. After recreating part of the PtERV1 retrovirus, it was reported that TRIM5α prevents the virus from entering human cells in vitro. While this cellular defense mechanism may have been very useful 4 million years ago when facing a PtERV1 epidemic
Epidemic
In epidemiology, an epidemic , occurs when new cases of a certain disease, in a given human population, and during a given period, substantially exceed what is expected based on recent experience...
, it has the side effect of leaving cells more susceptible to attack by the HIV-1 retrovirus. Recently, doubt has been cast over these conclusions. By using a PtERV1 capsid, which produces higher titer virus-like particles, Perez-Caballero et al. reported that PtERV1 is not restricted by either human or chimpanzee TRIM5α.
Clinical significance
Old World monkeyOld World monkey
The Old World monkeys or Cercopithecidae are a group of primates, falling in the superfamily Cercopithecoidea in the clade Catarrhini. The Old World monkeys are native to Africa and Asia today, inhabiting a range of environments from tropical rain forest to savanna, shrubland and mountainous...
s cannot be infected with HIV-1, the virus that causes AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
in human
Human
Humans are the only living species in the Homo genus...
s; they can be infected, however, with SIV
SIV
SIV or Siv may refer to:* Simian immunodeficiency virus, a virus found in primates and related to HIV* Siv, a character in the children's fiction book series Guardians of Ga'Hoole...
, a related virus. TRIM5α was isolated as a rhesus macaque
Rhesus Macaque
The Rhesus macaque , also called the Rhesus monkey, is one of the best-known species of Old World monkeys. It is listed as Least Concern in the IUCN Red List of Threatened Species in view of its wide distribution, presumed large population, and its tolerance of a broad range of habitats...
protein responsible for blocking infection by HIV-1.
The human version of TRIM5α does not target HIV-1, but can inhibit strains of the murine leukemia virus
Murine leukemia virus
The murine leukemia viruses are retroviruses named for their ability to cause cancer in murine hosts. Some MLVs may infect other vertebrates. MLVs include both exogenous and endogenous viruses...
(MLV) as well as equine infectious anemia virus (EIAV).
Prior to the discovery of TRIM5α as an antiviral protein, the inhibition phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
had been described and coined Ref1 (in human cells) and Lv1 (in monkey cells). This terminology is now largely abandoned.
A related protein, named TRIMCyp (or TRIM5-CypA), was isolated in owl monkeys, a species of New World monkeys, and shown to potently inhibit infection by HIV-1. A similar protein has arisen independently in Old World monkeys and has been identified in several species of macaque.
See also
- Peptidylprolyl isomerase APeptidylprolyl isomerase APeptidylprolyl isomerase A also known as cyclophilin A or rotamase A is an enzyme that in humans is encoded by the PPIA gene.- Function :...