TRIM5alpha

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 represents a novel and important innate immune defense against retroviruses, along with the APOBEC3 family of proteins, also recently discovered.cite journal | author = Cullen BR | title = Role and mechanism of action of the APOBEC3 family of antiretroviral resistance factors | journal = J. Virol. | volume = 80 | issue = 3 | pages = 1067–76 | year = 2006 | pmid = 16414984 | doi = 10.1128/JVI.80.3.1067-1076.2006 ] cite journal | author = Zhang KL, Mangeat B, Ortiz M, Zoete V, Trono D, Telenti A, Michielin O | title = Model structure of human APOBEC3G | journal = PLoS ONE | volume = 2 | issue = 4 | pages = e378 | year = 2007 | pmid = 17440614 | doi = 10.1371/journal.pone.0000378 ]

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.cite journal | author = Stremlau M, Owens CM, Perron MJ, Kiessling M, Autissier P, Sodroski J | title = The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys | journal = Nature | volume = 427 | issue = 6977 | pages = 848–53 | year = 2004 | pmid = 14985764 | doi = 10.1038/nature02343 ]

The human version of TRIM5α does not target HIV-1, but can inhibit strains of the murine leukemia virus (MLV)cite journal | author = Lee K, KewalRamani VN | title = In defense of the cell: TRIM5α interception of mammalian retroviruses | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 29 | pages = 10496–7 | year = 2004 | pmid = 15252204 | doi = 10.1073/pnas.0404066101 ] cite journal | author = Yap MW, Nisole S, Lynch C, Stoye JP | title = Trim5α protein restricts both HIV-1 and murine leukemia virus | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 29 | pages = 10786–91 | year = 2004 | pmid = 15249690 | doi = 10.1073/pnas.0402876101 ] as well as equine infectious anemia virus (EIAV).cite journal | author = Hatziioannou T, Perez-Caballero D, Yang A, Cowan S, Bieniasz PD | title = Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5α | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 29 | pages = 10774–9 | year = 2004 | pmid = 15249685 | doi = 10.1073/pnas.0402361101 ] cite journal | author = Keckesova Z, Ylinen LM, Towers GJ | title = The human and African green monkey TRIM5αgenes encode Ref1 and Lv1 retroviral restriction factor activities | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 29 | pages = 10780–5 | year = 2004 | pmid = 15249687 | doi = 10.1073/pnas.0402474101 ]

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.

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.cite journal | author = Reddy BA, Etkin LD, Freemont PS | title = A novel zinc finger coiled-coil domain in a family of nuclear proteins | journal = Trends Biochem. Sci. | volume = 17 | issue = 9 | pages = 344–5 | year = 1992 | pmid = 1412709 | doi = | issn = ] TRIM5α bears the C-terminal SPRY in addition to the other domains.

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.cite journal | author = Sayah DM, Sokolskaja E, Berthoux L, Luban J | title = Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1 | journal = Nature | volume = 430 | issue = 6999 | pages = 569–73 | year = 2004 | pmid = 15243629 | doi = 10.1038/nature02777 ] Astonishingly, a similar protein has arisen independently in Old World monkeys and has been identified in several species of macaque.cite journal | author = Wilson SJ, Webb BL, Ylinen LM, Verschoor E, Heeney JL, Towers GJ | title = Independent evolution of an antiviral TRIMCyp in rhesus macaques| journal = PNAS | volume = 105 | issue = 9 | pages = 3557–62 | year = 2008 | pmid = 18287035 | doi = 10.1073/pnas.0709003105 ]

Recently, Kaiser "et al" have discovered 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.cite journal | author = Kaiser SM, Malik HS, Emerman M | title = Restriction of an extinct retrovirus by the human TRIM5alpha antiviral protein | journal = Science | volume = 316 | issue = 5832 | pages = 1756–8 | year = 2007 | pmid = 17588933 | doi = 10.1126/science.1140579 ] 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 discovered 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.

Function

When a retrovirus has entered a host cell’s cytoplasm, it undergoes processes such as capsid uncoating and reverse transcription. TRIM5, which is 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. cite journal | author = Sebastian S, Luban J | title = TRIM5alpha selectively binds a restriction-sensitive retroviral capsid | journal = Retrovirology | volume = 2 | issue = | pages = 40 | year = 2005 | pmid = 15967037 | doi = 10.1186/1742-4690-2-40 ] cite journal | author = Stremlau M, Perron M, Lee M, Li Y, Song B, Javanbakht H, Diaz-Griffero F, Anderson DJ, Sundquist WI, Sodroski J | title = Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5alpha restriction factor | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 14 | pages = 5514–9 | year = 2006 | pmid = 16540544 | doi = 10.1073/pnas.0509996103 ] The exact mechanism of action has not been shown conclusively, but it seems to involve proteasome-dependent degradation.cite journal | author = Wu X, Anderson JL, Campbell EM, Joseph AM, Hope TJ | title = Proteasome inhibitors uncouple rhesus TRIM5alpha restriction of HIV-1 reverse transcription and infection | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 19 | pages = 7465–70 | year = 2006 | pmid = 16648264 | doi = 10.1073/pnas.0510483103 ]

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.cite journal | author = Berthoux L, Sebastian S, Sokolskaja E, Luban J | title = Cyclophilin A is required for TRIM5α-mediated resistance to HIV-1 in Old World monkey cells | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 102 | issue = 41 | pages = 14849–53 | year = 2005 | pmid = 16203999 | doi = 10.1073/pnas.0505659102 ]

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/SPRY domain.cite journal | author = Ohkura S, Yap MW, Sheldon T, Stoye JP | title = All three variable regions of the TRIM5alpha B30.2 domain can contribute to the specificity of retrovirus restriction | journal = J. Virol. | volume = 80 | issue = 17 | pages = 8554–65 | year = 2006 | pmid = 16912305 | doi = 10.1128/JVI.00688-06 ] Amino acid 332, which occurs within this domain, seems to play a critical role in determining the specificity of retrovirus restriction.cite journal | author = Yap MW, Nisole S, Stoye JP | title = A single amino acid change in the SPRY domain of human Trim5alpha leads to HIV-1 restriction | journal = Curr. Biol. | volume = 15 | issue = 1 | pages = 73–8 | year = 2005 | pmid = 15649369 | doi = 10.1016/j.cub.2004.12.042 ] cite journal | author = Kaiser SM, Malik HS, Emerman M | title = Restriction of an extinct retrovirus by the human TRIM5alpha antiviral protein | journal = Science | volume = 316 | issue = 5832 | pages = 1756–8 | year = 2007 | pmid = 17588933 | doi = 10.1126/science.1140579 ]

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