TRIM5alpha
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Location (UCSC) | Chr 11: 5.66 – 5.94 Mb | Chr 7: 103.99 – 104 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Tripartite motif-containing protein 5 also known as RING finger protein 88 is a protein that in humans is encoded by the TRIM5 gene.[5] The alpha isoform of this protein, TRIM5α, is a retrovirus restriction factor, which mediates a species-specific early block to retrovirus infection.
TRIM5α is composed of 493 amino acids which 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,[6][7] tetherin and TRIM22.
Structure
TRIM5α belongs to the TRIM protein family (TRIM stands for TRIpartite Motif); this family was first identified by Reddy in 1992 as a set of proteins which contain a RING type zinc finger domain, a B-box zinc binding domain, followed by a coiled-coil region.[8] TRIM5α bears the C-terminal PRY-SPRY or B30.2 domain in addition to the other domains.
Function and means of action
When a retrovirus enters the host cell cytosol, the retroviral capsid was previously believed to undergo uncoating, though this (the complete uncoating theory) is now doubted; rather the true picture is thought to be that capsid uncoating does indeed take place in the cytosol but that it is a process which takes place progressively as the capsid gets closer and closer to the nucleus, though the uncoating process usually, but not always, completes in the nucleus.[9] Further, the viral genome in the capsid is reverse transcribed inside the viral capsid[10] to enable the production of daughter virions.
TRIM5α is present in the cytosol. It recognizes motifs within viral capsid proteins, which causes the TRIM5α to smother the (not yet uncoated) viral capsid in a tessilatory manner so as to form a repeating regular hexagonal net, two sides of each hexagon being made up of two spokes of a three-way hub and spoke trimer[11] and consequently by means of that smothering to interfere with any viral capsid uncoating process, thereby (1) preventing transport of the viral genome into the host cell nucleus and (2) also preventing successful reverse transcription of viral RNA into a length of DNA to be spliced into the host genome to enable expression of viral proteins via a transcrption process.[12][13] The exact mechanism of action has not been shown conclusively, but capsid protein from restricted viruses (that is viruses which are the subject of TRIM5α intervention) is removed by proteasome-dependent degradation.[14] The TRIM5α, once formed into its highly regular reticulatory net recruits ubiquitin for this purpose, which, in turn engages the proteasome.[11]
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.[15]
The "specificity" of restriction, that is, whether a given retrovirus can be targeted by TRIM5α, is entirely determined by the
TRIM5α may have played a critical role in the human immune defense system about 4 million years ago, when the retrovirus
Clinical significance
Humans also have a TRIM5α, but it is not well enough tuned to mediate a sufficient response. However, the human version of TRIM5α can inhibit strains of the murine leukemia virus (MLV)[21][22] as well as equine infectious anemia virus (EIAV).[23][24]
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 the
It was recently described that interferon-α-mediated stimulation of the immunoproteasome enables human TRIM5α for effective capsid-dependent inhibition of HIV-1 DNA synthesis and infection.[28]
Notes and references
- ^ a b c GRCh38: Ensembl release 89: ENSG00000132256 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000057143 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 11331580.
- PMID 16414984.
- PMID 17440614.
- PMID 1412709.
- PMID 24130490.
- PMID 33033190.
- ^ PMID 30503508.
- PMID 15967037.
- PMID 16540544.
- PMID 16648264.
- PMID 16203999.
- PMID 16912305.
- S2CID 1910582.
- ^ S2CID 33225147.
- PMID 18927623.
- PMID 32930662.
- PMID 15252204.
- PMID 15249690.
- PMID 15249685.
- PMID 15249687.
- S2CID 4379907.
- PMID 18287035.
- PMID 18287033.
- PMID 30886358.
External links
- "UniProtKB/Swiss-Prot entry Q587N7 (TRIM5_CERAE) Tripartite motif-containing protein 5". Swiss Institute of Bioinformatics. Retrieved 2008-02-19.
- "NCBI Sequence Viewer v2.0". National Center for Biotechnology Information. Retrieved 2008-02-19.
- Minkel JR (2007-06-21). "Defense against Ancient Virus Opened Door to HIV". Scientific American. Retrieved 2008-02-19.
- Hopkin M (2007-06-26). "Access : Ancient disease resistance made us vulnerable to HIV". Nature News. S2CID 84816126. Retrieved 2008-02-19.
- Overview of all the structural information available in the PDB for UniProt: Q9C035 (Tripartite motif-containing protein 5) at the PDBe-KB.