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Tripartite motif-containing 5
Identifiers
Symbols TRIM5; RNF88; TRIM5alpha
External IDs OMIM608487 MGI2441735 HomoloGene75345 GeneCards: TRIM5 Gene
RNA expression pattern
PBB GE TRIM5 210705 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 85363 319236
Ensembl ENSG00000132256 n/a
UniProt Q9C035 n/a
RefSeq (mRNA) NM_033034 NM_175677
RefSeq (protein) NP_149023 NP_783608
Location (UCSC) Chr 11:
5.64 - 5.85 Mb
n/a
PubMed search [1] [2]

TRIM5α, also written as TRIM5alpha or TRIM5-alpha, is a protein composed of 493 amino acids that is found in the cells of most primates. It is clear that TRIM5α is an intrinsic immune factor important in the innate immune defense against retroviruses, along with the APOBEC3 family of proteins [1][2], tetherin and TRIM22.

Contents

Structure

TRIM5α belongs to the TRIM protein family (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.[3] 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. [4][5] The exact mechanism of action has not been shown conclusively, but capsid protein from restricted viruses is removed by proteasome-dependent degradation.[6]

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.[7]

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.[8] Amino acid 332, which occurs within this domain, seems to play a critical role in determining the specificity of retrovirus restriction.[9][10]

Kaiser et al. have suggested that 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.[10] 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 the conclusions made by Kaiser et al. 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. [11]

Clinical significance

Old World monkeys cannot be infected with HIV-1, the virus that causes AIDS in humans; they can be infected, however, with SIV, a related virus. In 2004, Stremlau et al. isolated TRIM5α as a rhesus macaque protein responsible for blocking infection by HIV-1.[12]

The human version of TRIM5α does not target HIV-1, but can inhibit strains of the murine leukemia virus (MLV)[13][14] as well as equine infectious anemia virus (EIAV).[15][16]

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.

Also in 2004, 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.[17] Astonishingly, a similar protein has arisen independently in Old World monkeys and has been identified in several species of macaque.[18]

References

  1. ^ Cullen BR (2006). "Role and mechanism of action of the APOBEC3 family of antiretroviral resistance factors". J. Virol. 80 (3): 1067–76. doi:10.1128/JVI.80.3.1067-1076.2006. PMID 16414984.  
  2. ^ Zhang KL, Mangeat B, Ortiz M, Zoete V, Trono D, Telenti A, Michielin O (2007). "Model structure of human APOBEC3G". PLoS ONE 2 (4): e378. doi:10.1371/journal.pone.0000378. PMID 17440614.  
  3. ^ Reddy BA, Etkin LD, Freemont PS (1992). "A novel zinc finger coiled-coil domain in a family of nuclear proteins". Trends Biochem. Sci. 17 (9): 344–5. doi:10.1016/0968-0004(92)90308-V. PMID 1412709.  
  4. ^ Sebastian S, Luban J (2005). "TRIM5alpha selectively binds a restriction-sensitive retroviral capsid". Retrovirology 2: 40. doi:10.1186/1742-4690-2-40. PMID 15967037.  
  5. ^ Stremlau M, Perron M, Lee M, Li Y, Song B, Javanbakht H, Diaz-Griffero F, Anderson DJ, Sundquist WI, Sodroski J (2006). "Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5alpha restriction factor". Proc. Natl. Acad. Sci. U.S.A. 103 (14): 5514–9. doi:10.1073/pnas.0509996103. PMID 16540544.  
  6. ^ Wu X, Anderson JL, Campbell EM, Joseph AM, Hope TJ (2006). "Proteasome inhibitors uncouple rhesus TRIM5alpha restriction of HIV-1 reverse transcription and infection". Proc. Natl. Acad. Sci. U.S.A. 103 (19): 7465–70. doi:10.1073/pnas.0510483103. PMID 16648264.  
  7. ^ Berthoux L, Sebastian S, Sokolskaja E, Luban J (2005). "Cyclophilin A is required for TRIM5α-mediated resistance to HIV-1 in Old World monkey cells". Proc. Natl. Acad. Sci. U.S.A. 102 (41): 14849–53. doi:10.1073/pnas.0505659102. PMID 16203999.  
  8. ^ Ohkura S, Yap MW, Sheldon T, Stoye JP (2006). "All three variable regions of the TRIM5alpha B30.2 domain can contribute to the specificity of retrovirus restriction". J. Virol. 80 (17): 8554–65. doi:10.1128/JVI.00688-06. PMID 16912305.  
  9. ^ Yap MW, Nisole S, Stoye JP (2005). "A single amino acid change in the SPRY domain of human Trim5alpha leads to HIV-1 restriction". Curr. Biol. 15 (1): 73–8. doi:10.1016/j.cub.2004.12.042. PMID 15649369.  
  10. ^ a b Kaiser SM, Malik HS, Emerman M (2007). "Restriction of an extinct retrovirus by the human TRIM5alpha antiviral protein". Science 316 (5832): 1756–8. doi:10.1126/science.1140579. PMID 17588933.  
  11. ^ Perez-Caballero D, Soll SJ, Bieniasz PD (2008). "Evidence for restriction of ancient primate gammaretroviruses by APOBEC3 but not TRIM5alpha proteins.". PLoS Pathog.. PMID 18927623.  
  12. ^ Stremlau M, Owens CM, Perron MJ, Kiessling M, Autissier P, Sodroski J (2004). "The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys". Nature 427 (6977): 848–53. doi:10.1038/nature02343. PMID 14985764.  
  13. ^ Lee K, KewalRamani VN (2004). "In defense of the cell: TRIM5α interception of mammalian retroviruses". Proc. Natl. Acad. Sci. U.S.A. 101 (29): 10496–7. doi:10.1073/pnas.0404066101. PMID 15252204.  
  14. ^ Yap MW, Nisole S, Lynch C, Stoye JP (2004). "Trim5α protein restricts both HIV-1 and murine leukemia virus". Proc. Natl. Acad. Sci. U.S.A. 101 (29): 10786–91. doi:10.1073/pnas.0402876101. PMID 15249690.  
  15. ^ Hatziioannou T, Perez-Caballero D, Yang A, Cowan S, Bieniasz PD (2004). "Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5α". Proc. Natl. Acad. Sci. U.S.A. 101 (29): 10774–9. doi:10.1073/pnas.0402361101. PMID 15249685.  
  16. ^ Keckesova Z, Ylinen LM, Towers GJ (2004). "The human and African green monkey TRIM5αgenes encode Ref1 and Lv1 retroviral restriction factor activities". Proc. Natl. Acad. Sci. U.S.A. 101 (29): 10780–5. doi:10.1073/pnas.0402474101. PMID 15249687.  
  17. ^ Sayah DM, Sokolskaja E, Berthoux L, Luban J (2004). "Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1". Nature 430 (6999): 569–73. doi:10.1038/nature02777. PMID 15243629.  
  18. ^ Wilson SJ, Webb BL, Ylinen LM, Verschoor E, Heeney JL, Towers GJ (2008). "Independent evolution of an antiviral TRIMCyp in rhesus macaques". PNAS 105 (9): 3557–62. doi:10.1073/pnas.0709003105. PMID 18287035.  

External links

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