Biology:TRIM5alpha

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Tripartite motif-containing protein 5 also known as RING finger protein 88 is a protein that in humans is encoded by the TRIM5 gene.[1] 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,[2][3] 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.[4] TRIM5α bears the C-terminal PRY-SPRY or B30.2 domain in addition to the other domains.

Function

TRIM5α is a cytosolic protein that recognizes specific motifs on incoming viral capsids. Upon recognition, TRIM5α assembles into a hexagonal lattice that coats the capsid surface in a highly regular, tessellated manner. Each hexagon in this lattice is formed by interactions between trimeric hub-and-spoke structures.[5] This coating disrupts the normal uncoating process, thereby (1) blocking nuclear import of the viral genome and (2) interfering with reverse transcription of viral RNA into DNA, which is required for integration into the host genome and subsequent viral gene expression.[6][7]

While the full mechanism remains incompletely understood, it is known that TRIM5α promotes proteasome-dependent degradation of capsid proteins from restricted viruses.[8] This process involves the recruitment of ubiquitin by the TRIM5α lattice, which subsequently targets the capsid for degradation by the proteasome.[5] Additional host proteins may participate in TRIM5α-mediated restriction, though definitive evidence is still lacking. One known cofactor is Cyclophilin A, which is required for TRIM5α-mediated HIV-1 inhibition in Old World monkey cells.[9] The specificity of TRIM5α-mediated restriction—that is, which retroviruses are targeted—is determined by the amino acid sequence of its C-terminal domain, known as the B30.2 or PRY-SPRY domain.[10] Within this domain, amino acid residue 332 plays a particularly important role in determining which retroviruses are restricted.[11][12]

When a retrovirus enters the host cell cytosol, its capsid was once thought to undergo complete uncoating immediately. However, this model is now considered oversimplified. Current understanding suggests that uncoating is a progressive process that begins in the cytosol and continues as the capsid approaches the nucleus, with final disassembly typically—but not always—occurring within the nucleus.[13] Reverse transcription of the viral genome also occurs within the intact or partially uncoated capsid, producing viral DNA necessary for the formation of daughter virions.[14]

Clinical significance

PtERV1 resistance

TRIM5α may have played a critical role in the human immune defense system about 4 million years ago, when the retrovirus PtERV1 was infecting the ancestors of modern chimpanzees.[12] 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.[15]

HIV-1 resistance

Rhesus macaques, a species of Old World monkeys, are almost completely resistant to HIV-1, the virus that causes AIDS in humans.[16] This resistance is due to a version of the antiviral protein TRIM5α that binds the HIV-1 capsid with high affinity and rapidly induces its degradation, effectively neutralizing the virus.

Humans also express TRIM5α, but the human variant is not sufficiently adapted to block HIV-1 effectively. However, it can restrict other retroviruses, including certain strains of murine leukemia virus (MLV)[17][18] and equine infectious anemia virus (EIAV).[19][20] Before TRIM5α was identified as the underlying restriction factor, this antiviral activity had been observed and termed Ref1 in human cells and Lv1 in monkey cells. These terms are now largely obsolete.

A related protein, known as TRIMCyp (or TRIM5-CypA), was discovered in the owl monkey, a species of New World monkey. This fusion protein potently inhibits HIV-1 infection.[21] A similar TRIMCyp protein has independently evolved in several species of Old World monkeys, including various macaques.[22][23]

More recently, it has been shown that stimulation with interferon-α can activate the immunoproteasome, enabling human TRIM5α to effectively block HIV-1 by interfering with capsid-dependent DNA synthesis and infection.[24]

Notes and references

  1. ↑ "The tripartite motif family identifies cell compartments". The EMBO Journal 20 (9): 2140–2151. May 2001. doi:10.1093/emboj/20.9.2140. PMID 11331580. 
  2. ↑ "Role and mechanism of action of the APOBEC3 family of antiretroviral resistance factors". Journal of Virology 80 (3): 1067–1076. Feb 2006. doi:10.1128/JVI.80.3.1067-1076.2006. PMID 16414984. 
  3. ↑ Aballay, Alejandro, ed (Apr 2007). "Model structure of human APOBEC3G". PLOS ONE 2 (4): e378. doi:10.1371/journal.pone.0000378. PMID 17440614. Bibcode: 2007PLoSO...2..378Z. 
  4. ↑ "A novel zinc finger coiled-coil domain in a family of nuclear proteins". Trends in Biochemical Sciences 17 (9): 344–345. Sep 1992. doi:10.1016/0968-0004(92)90308-V. PMID 1412709. 
  5. ↑ 5.0 5.1 "Trivalent RING Assembly on Retroviral Capsids Activates TRIM5 Ubiquitination and Innate Immune Signaling.". Cell Host & Microbe 24 (6): 761–775.e6. Dec 2018. doi:10.1016/j.chom.2018.10.007. PMID 30503508. 
  6. ↑ "TRIM5alpha selectively binds a restriction-sensitive retroviral capsid". Retrovirology 2. Jun 2005. doi:10.1186/1742-4690-2-40. PMID 15967037. 
  7. ↑ "Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5alpha restriction factor". Proceedings of the National Academy of Sciences of the United States of America 103 (14): 5514–5519. Apr 2006. doi:10.1073/pnas.0509996103. PMID 16540544. 
  8. ↑ "Proteasome inhibitors uncouple rhesus TRIM5alpha restriction of HIV-1 reverse transcription and infection". Proceedings of the National Academy of Sciences of the United States of America 103 (19): 7465–7470. May 2006. doi:10.1073/pnas.0510483103. PMID 16648264. Bibcode: 2006PNAS..103.7465W. 
  9. ↑ "Cyclophilin A is required for TRIM5α-mediated resistance to HIV-1 in Old World monkey cells". Proceedings of the National Academy of Sciences of the United States of America 102 (41): 14849–14853. Oct 2005. doi:10.1073/pnas.0505659102. PMID 16203999. Bibcode: 2005PNAS..10214849B. 
  10. ↑ "All three variable regions of the TRIM5alpha B30.2 domain can contribute to the specificity of retrovirus restriction". Journal of Virology 80 (17): 8554–8565. Sep 2006. doi:10.1128/JVI.00688-06. PMID 16912305. 
  11. ↑ "A single amino acid change in the SPRY domain of human Trim5alpha leads to HIV-1 restriction". Current Biology 15 (1): 73–78. Jan 2005. doi:10.1016/j.cub.2004.12.042. PMID 15649369. Bibcode: 2005CBio...15...73Y. 
  12. ↑ 12.0 12.1 "Restriction of an extinct retrovirus by the human TRIM5alpha antiviral protein". Science 316 (5832): 1756–1758. Jun 2007. doi:10.1126/science.1140579. PMID 17588933. Bibcode: 2007Sci...316.1756K. 
  13. ↑ "Nucleoporin NUP153 Phenylalanine-Glycine Motifs Engage a Common Binding Pocket within the HIV-1 Capsid Protein to Mediate Lentiviral Infectivity". PLOS Pathogens 9 (10). 2013. doi:10.1371/journal.ppat.1003693. PMID 24130490. 
  14. ↑ "Reconstitution and visualization of HIV-1 capsid-dependent replication and integration in vitro.". Science 370 (6513): 1–11. Oct 2020. doi:10.1126/science.abc8420. PMID 33033190. 
  15. ↑ Hope, Thomas J., ed (Oct 2008). "Evidence for restriction of ancient primate gammaretroviruses by APOBEC3 but not TRIM5alpha proteins". PLOS Pathogens 4 (10). doi:10.1371/journal.ppat.1000181. PMID 18927623. 
  16. ↑ "Mutational resilience of antiviral restriction favors primate TRIM5α in host-virus evolutionary arms races". eLife 9. 2020-09-15. doi:10.7554/eLife.59988. ISSN 2050-084X. PMID 32930662. 
  17. ↑ "In defense of the cell: TRIM5α interception of mammalian retroviruses". Proceedings of the National Academy of Sciences of the United States of America 101 (29): 10496–10497. Jul 2004. doi:10.1073/pnas.0404066101. PMID 15252204. Bibcode: 2004PNAS..10110496L. 
  18. ↑ "Trim5α protein restricts both HIV-1 and murine leukemia virus". Proceedings of the National Academy of Sciences of the United States of America 101 (29): 10786–10791. Jul 2004. doi:10.1073/pnas.0402876101. PMID 15249690. Bibcode: 2004PNAS..10110786Y. 
  19. ↑ "Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5α". Proceedings of the National Academy of Sciences of the United States of America 101 (29): 10774–10779. Jul 2004. doi:10.1073/pnas.0402361101. PMID 15249685. Bibcode: 2004PNAS..10110774H. 
  20. ↑ "The human and African green monkey TRIM5α genes encode Ref1 and Lv1 retroviral restriction factor activities". Proceedings of the National Academy of Sciences of the United States of America 101 (29): 10780–10785. Jul 2004. doi:10.1073/pnas.0402474101. PMID 15249687. Bibcode: 2004PNAS..10110780K. 
  21. ↑ "Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1". Nature 430 (6999): 569–573. Jul 2004. doi:10.1038/nature02777. PMID 15243629. Bibcode: 2004Natur.430..569S. 
  22. ↑ "Independent evolution of an antiviral TRIMCyp in rhesus macaques". Proceedings of the National Academy of Sciences of the United States of America 105 (9): 3557–3562. Mar 2008. doi:10.1073/pnas.0709003105. PMID 18287035. Bibcode: 2008PNAS..105.3557W. 
  23. ↑ "TRIMCyp expression in Old World primates Macaca nemestrina and Macaca fascicularis". Proceedings of the National Academy of Sciences of the United States of America 105 (9): 3569–3574. Mar 2008. doi:10.1073/pnas.0709511105. PMID 18287033. Bibcode: 2008PNAS..105.3569B. 
  24. ↑ "Immunoproteasome activation enables human TRIM5α restriction of HIV-1". Nature Microbiology 4 (6): 933–940. June 2019. doi:10.1038/s41564-019-0402-0. PMID 30886358. 

See also

  • Peptidylprolyl isomerase A



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