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TRIM5alpha



tripartite motif-containing protein 5 alpha
Identifiers
Symbol TRIM5α
Alt. Symbols RNF88
Entrez 85363
HUGO 16276
OMIM 608487
RefSeq uc001mbm.1
UniProt Q9C035
Other data
Locus Chr. 11 p15

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[1][2].

Additional recommended knowledge

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[3]. The human version of TRIM5α does not target HIV-1, but can inhibit strains of the murine leukemia virus (MLV)[4][5] as well as equine infectious anemia virus (EIAV)[6][7].

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[8]. 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[9].

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[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 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 cell cytoplasm, it undergoes processes known as capsid uncoating and reverse transcription. TRIM5α, which is present in the cytoplasm, recognizes motifs within the capsid proteins and interferes with the uncoating process, thereby preventing successful reverse transcription and transport to the cell nucleus of the viral genome.[11][12]. The exact mechanism of action has not been shown conclusively, but it seems to involve proteasome-dependent degradation[13].

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[14].

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[15]. Amino acid 332, which occurs within this domain, seems to play a critical role in determining the specificity of retrovirus restriction[16][17].

References

  1. ^ Cullen, Bryan (February 2006). "Role and Mechanism of Action of the APOBEC3 Family of Antiretroviral Resistance Factors". Journal of Virology 80 (3): 1067-1076.
  2. ^ Zhang, Kun-Lin (April 2007). "Model Structure of Human APOBEC3G". PLoS ONE 2 (4).
  3. ^ Stremlau, Matthew (February 2004). "The cytoplasmic body component TRIM5α restricts HIV-1 infection in Old World monkeys". Nature 427: 848-853.
  4. ^ Lee, Kyeongeun (July 2004). "In defense of the cell: TRIM5α interception of mammalian retroviruses". PNAS 101 (29): 10496-10497.
  5. ^ Yap, Melvyn (July 2004). "Trim5α protein restricts both HIV-1 and murine leukemia virus". PNAS 101 (29): 10786-10791.
  6. ^ Hatziioannou, Theodora (July 2004). "Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5α". PNAS 101 (29): 10774-10779.
  7. ^ Keckesova, Zuzana (July 2004). "The human and African green monkey TRIM5α genes encode Ref1 and Lv1 retroviral restriction factor activities". PNAS 101 (29): 10780-10785.
  8. ^ Reddy (September 1992). "A novel zinc finger coiled-coil domain in a family of nuclear proteins". Trends in Biochemical Sciences 17 (9): 344-345.
  9. ^ Sayah, David (July 2004). "Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1". Nature 430: 569-573.
  10. ^ Kaiser, Shariser (June 2007). "Restriction of an Extinct Retrovirus by the Human TRIM5α Antiviral Protein". Science 316 (5832): 1756-1758.
  11. ^ Sebastian, Sarah (June 2005). "TRIM5α selectively binds a restriction-sensitive retroviral capsid". Retrovirology 2: 40.
  12. ^ Stremlau, Matthew (April 2006). "Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5α restriction factor". PNAS 103 (14): 5514-5519.
  13. ^ Wu, Xiaolu (May 2006). "Proteasome inhibitors uncouple rhesus TRIM5α restriction of HIV-1 reverse transcription and infection". PNAS 103 (19): 7465-7470.
  14. ^ Berthoux, Lionel (October 2005). "Cyclophilin A is required for TRIM5α-mediated resistance to HIV-1 in Old World monkey cells". PNAS 102 (41): 14849-14853.
  15. ^ Ohkura, Sadayuki (September 2006). "All Three Variable Regions of the TRIM5α B30.2 Domain Can Contribute to the Specificity of Retrovirus Restriction". Journal of Virology 80 (17): 8554-8565.
  16. ^ Yap, Melvyn (January 2005). "A Single Amino Acid Change in the SPRY Domain of Human Trim5α Leads to HIV-1 Restriction". Current Biology 15.
  17. ^ Kaiser, Shariser (June 2007). "Restriction of an Extinct Retrovirus by the Human TRIM5α Antiviral Protein". Science 316 (5832): 1756-1758.
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "TRIM5alpha". A list of authors is available in Wikipedia.
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