TRIM5alpha

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TRIM5
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTRIM5, RNF88, TRIM5alpha, tripartite motif containing 5
External IDsOMIM: 608487; MGI: 4821183; HomoloGene: 75345; GeneCards: TRIM5; OMA:TRIM5 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

85363

319236

Ensembl

ENSG00000132256

ENSMUSG00000057143

UniProt

Q9C035

D3Z3L3

RefSeq (mRNA)

NM_033034
NM_033092
NM_033093

NM_001146007
NM_175677

RefSeq (protein)

NP_149023
NP_149083
NP_149084

NP_001139479
NP_783608

Location (UCSC)Chr 11: 5.66 – 5.94 MbChr 7: 103.99 – 104 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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

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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

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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.[9] 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.[10][11]

While the full mechanism remains incompletely understood, it is known that TRIM5α promotes proteasome-dependent degradation of capsid proteins from restricted viruses.[12] This process involves the recruitment of ubiquitin by the TRIM5α lattice, which subsequently targets the capsid for degradation by the proteasome.[9] 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.[13] 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.[14] Within this domain, amino acid residue 332 plays a particularly important role in determining which retroviruses are restricted.[15][16]

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.[17] 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.[18]

Clinical significance

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PtERV1 resistance

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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.[16] 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.[19]

HIV-1 resistance

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Rhesus macaques, a species of Old World monkeys, are almost completely resistant to HIV-1, the virus that causes AIDS in humans.[20] 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)[21][22] and equine infectious anemia virus (EIAV).[23][24] 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.[25] A similar TRIMCyp protein has independently evolved in several species of Old World monkeys, including various macaques.[26][27]

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.[28]

Notes and references

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000132256 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000057143 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, et al. (May 2001). "The tripartite motif family identifies cell compartments". The EMBO Journal. 20 (9): 2140–2151. doi:10.1093/emboj/20.9.2140. PMC 125245. PMID 11331580.
  6. ^ Cullen BR (Feb 2006). "Role and mechanism of action of the APOBEC3 family of antiretroviral resistance factors". Journal of Virology. 80 (3): 1067–1076. doi:10.1128/JVI.80.3.1067-1076.2006. PMC 1346961. PMID 16414984.
  7. ^ Zhang KL, Mangeat B, Ortiz M, Zoete V, Trono D, Telenti A, et al. (Apr 2007). Aballay A (ed.). "Model structure of human APOBEC3G". Plos One. 2 (4): e378. Bibcode:2007PLoSO...2..378Z. doi:10.1371/journal.pone.0000378. PMC 1849894. PMID 17440614. Open access icon
  8. ^ Reddy BA, Etkin LD, Freemont PS (Sep 1992). "A novel zinc finger coiled-coil domain in a family of nuclear proteins". Trends in Biochemical Sciences. 17 (9): 344–345. doi:10.1016/0968-0004(92)90308-V. PMID 1412709.
  9. ^ a b Fletcher AJ, Vaysburd M, Maslen S, Zeng J, Skehel JM, Towers GJ, et al. (Dec 2018). "Trivalent RING Assembly on Retroviral Capsids Activates TRIM5 Ubiquitination and Innate Immune Signaling". Cell Host & Microbe. 24 (6): 761–775.e6. doi:10.1016/j.chom.2018.10.007. PMC 6299210. PMID 30503508.
  10. ^ Sebastian S, Luban J (Jun 2005). "TRIM5alpha selectively binds a restriction-sensitive retroviral capsid". Retrovirology. 2: 40. doi:10.1186/1742-4690-2-40. PMC 1166576. PMID 15967037.
  11. ^ Stremlau M, Perron M, Lee M, Li Y, Song B, Javanbakht H, et al. (Apr 2006). "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. doi:10.1073/pnas.0509996103. PMC 1459386. PMID 16540544.
  12. ^ Wu X, Anderson JL, Campbell EM, Joseph AM, Hope TJ (May 2006). "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. Bibcode:2006PNAS..103.7465W. doi:10.1073/pnas.0510483103. PMC 1464362. PMID 16648264.
  13. ^ Berthoux L, Sebastian S, Sokolskaja E, Luban J (Oct 2005). "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. Bibcode:2005PNAS..10214849B. doi:10.1073/pnas.0505659102. PMC 1239943. PMID 16203999.
  14. ^ Ohkura S, Yap MW, Sheldon T, Stoye JP (Sep 2006). "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. doi:10.1128/JVI.00688-06. PMC 1563890. PMID 16912305.
  15. ^ Yap MW, Nisole S, Stoye JP (Jan 2005). "A single amino acid change in the SPRY domain of human Trim5alpha leads to HIV-1 restriction". Current Biology : CB. 15 (1): 73–78. Bibcode:2005CBio...15...73Y. doi:10.1016/j.cub.2004.12.042. PMID 15649369. S2CID 1910582.
  16. ^ a b Kaiser SM, Malik HS, Emerman M (Jun 2007). "Restriction of an extinct retrovirus by the human TRIM5alpha antiviral protein". Science. 316 (5832). New York, N.Y.: 1756–1758. Bibcode:2007Sci...316.1756K. doi:10.1126/science.1140579. PMID 17588933. S2CID 33225147.
  17. ^ Matreyek KA, Yücel SS, Li X, Engelman A (2013). "Nucleoporin NUP153 Phenylalanine-Glycine Motifs Engage a Common Binding Pocket within the HIV-1 Capsid Protein to Mediate Lentiviral Infectivity". Plos Pathogens. 9 (10): e1003693. doi:10.1371/journal.ppat.1003693. PMC 3795039. PMID 24130490.
  18. ^ Christensen DE, Ganser-Pornillos BK, Johnson JS, Pornillos O, Sundquist WI (Oct 2020). "Reconstitution and visualization of HIV-1 capsid-dependent replication and integration in vitro". Science. 370 (6513). New York, N.Y.: 1–11. doi:10.1126/science.abc8420. PMC 6299210. PMID 33033190.
  19. ^ Perez-Caballero D, Soll SJ, Bieniasz PD (Oct 2008). Hope TJ (ed.). "Evidence for restriction of ancient primate gammaretroviruses by APOBEC3 but not TRIM5alpha proteins". Plos Pathogens. 4 (10): e1000181. doi:10.1371/journal.ppat.1000181. PMC 2564838. PMID 18927623. Open access icon
  20. ^ Tenthorey JL, Young C, Sodeinde A, Emerman M, Malik HS (2020-09-15). Schoggins JW, Weigel D, Berthoux L (eds.). "Mutational resilience of antiviral restriction favors primate TRIM5α in host-virus evolutionary arms races". Elife. 9: e59988. doi:10.7554/eLife.59988. ISSN 2050-084X. PMC 7492085. PMID 32930662.
  21. ^ Lee K, KewalRamani VN (Jul 2004). "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. doi:10.1073/pnas.0404066101. PMC 489964. PMID 15252204.
  22. ^ Yap MW, Nisole S, Lynch C, Stoye JP (Jul 2004). "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. Bibcode:2004PNAS..10110786Y. doi:10.1073/pnas.0402876101. PMC 490012. PMID 15249690.
  23. ^ Hatziioannou T, Perez-Caballero D, Yang A, Cowan S, Bieniasz PD (Jul 2004). "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. Bibcode:2004PNAS..10110774H. doi:10.1073/pnas.0402361101. PMC 490010. PMID 15249685.
  24. ^ Keckesova Z, Ylinen LM, Towers GJ (Jul 2004). "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. Bibcode:2004PNAS..10110780K. doi:10.1073/pnas.0402474101. PMC 490011. PMID 15249687.
  25. ^ Sayah DM, Sokolskaja E, Berthoux L, Luban J (Jul 2004). "Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1". Nature. 430 (6999): 569–573. Bibcode:2004Natur.430..569S. doi:10.1038/nature02777. PMID 15243629. S2CID 4379907.
  26. ^ Wilson SJ, Webb BL, Ylinen LM, Verschoor E, Heeney JL, Towers GJ (Mar 2008). "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. Bibcode:2008PNAS..105.3557W. doi:10.1073/pnas.0709003105. PMC 2265179. PMID 18287035.
  27. ^ Brennan G, Kozyrev Y, Hu SL (Mar 2008). "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. Bibcode:2008PNAS..105.3569B. doi:10.1073/pnas.0709511105. PMC 2265124. PMID 18287033.
  28. ^ Jimenez-Guardeño JM, Apolonia L, Betancor G, Malim MH (June 2019). "Immunoproteasome activation enables human TRIM5α restriction of HIV-1". Nature Microbiology. 4 (6): 933–940. doi:10.1038/s41564-019-0402-0. PMC 6544544. PMID 30886358.
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See also

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