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'''Tripartite motif-containing protein 5''' also known as '''RING finger protein 88''' is a [[protein]] that in humans is encoded by the '''''TRIM5''''' [[gene]].<ref name="pmid11331580">{{cite journal | vauthors = Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S, Guffanti A, Minucci S, Pelicci PG, Ballabio A | title = The tripartite motif family identifies cell compartments | journal = EMBO J. | volume = 20 | issue = 9 | pages = 2140–51 |date=May 2001 | pmid = 11331580 | pmc = 125245 | doi = 10.1093/emboj/20.9.2140 }}</ref> The alpha isoform of this protein, '''TRIM5α''', is a [[retrovirus]] restriction factor, which mediates a species-specific early block to retrovirus infection.
'''Tripartite motif-containing protein 5''' also known as '''RING finger protein 88''' is a [[protein]] that in humans is encoded by the '''''TRIM5''''' [[gene]].<ref name="Reymond_2001">{{cite journal | vauthors = Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S, Guffanti A, Minucci S, Pelicci PG, Ballabio A | title = The tripartite motif family identifies cell compartments | journal = The EMBO Journal | volume = 20 | issue = 9 | pages = 2140–2151 | date = May 2001 | pmid = 11331580 | pmc = 125245 | doi = 10.1093/emboj/20.9.2140 }}</ref> 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 acid]]s which is found in the [[cell (biology)|cells]] of most [[primate]]s. TRIM5α is an intrinsic immune factor important in the [[innate immune system|innate immune defense]] against retroviruses, along with the [[APOBEC]] family of proteins,<ref name="pmid16414984">{{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 | pmc = 1346961 }}</ref><ref name="pmid17440614">{{cite journal | vauthors = 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 | pmc = 1849894 | editor1-last = Aballay | editor1-first = Alejandro | bibcode = 2007PLoSO...2..378Z | doi-access = free }} {{open access}}</ref> [[tetherin]] and [[TRIM22]].
TRIM5α is composed of 493 [[amino acid]]s which is found in the [[cell (biology)|cells]] of most [[primate]]s. TRIM5α is an intrinsic immune factor important in the [[innate immune system|innate immune defense]] against retroviruses, along with the [[APOBEC]] family of proteins,<ref name="Cullen_2006">{{cite journal | vauthors = Cullen BR | title = Role and mechanism of action of the APOBEC3 family of antiretroviral resistance factors | journal = Journal of Virology | volume = 80 | issue = 3 | pages = 1067–1076 | date = Feb 2006 | pmid = 16414984 | pmc = 1346961 | doi = 10.1128/JVI.80.3.1067-1076.2006 }}</ref><ref name="Zhang_2007">{{cite journal | vauthors = 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 | date = Apr 2007 | pmid = 17440614 | pmc = 1849894 | doi = 10.1371/journal.pone.0000378 | editor1-last = Aballay | editor1-first = Alejandro | bibcode = 2007PLoSO...2..378Z | doi-access = free }} {{open access}}</ref> [[tetherin]] and [[TRIM22]].


== Structure ==
== Structure ==


TRIM5α belongs to the [[tripartite motif family|TRIM protein family]] (TRIM stands for '''TRI'''partite '''M'''otif); this family was first identified by Reddy in 1992 as a set of proteins which contain a [[RING finger domain|RING type zinc finger]] domain, a B-box zinc binding domain, followed by a [[coiled coil|coiled-coil region]].<ref name="pmid1412709">{{cite journal | vauthors = 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 = 10.1016/0968-0004(92)90308-V }}</ref> TRIM5α bears the [[C-terminus|C-terminal]] PRY-SPRY or B30.2 domain in addition to the other domains.
TRIM5α belongs to the [[tripartite motif family|TRIM protein family]] (TRIM stands for '''TRI'''partite '''M'''otif); this family was first identified by Reddy in 1992 as a set of proteins which contain a [[RING finger domain|RING type zinc finger]] domain, a B-box zinc binding domain, followed by a [[coiled coil|coiled-coil region]].<ref name="Reddy_1992">{{cite journal | vauthors = Reddy BA, Etkin LD, Freemont PS | title = A novel zinc finger coiled-coil domain in a family of nuclear proteins | journal = Trends in Biochemical Sciences | volume = 17 | issue = 9 | pages = 344–345 | date = Sep 1992 | pmid = 1412709 | doi = 10.1016/0968-0004(92)90308-V }}</ref> TRIM5α bears the [[C-terminus|C-terminal]] PRY-SPRY or B30.2 domain in addition to the other domains.


==Function and means of action==
== Function ==


When a [[retrovirus]] enters the host cell [[cytosol]], the retroviral [[capsid]] was previously believed to undergo uncoating, though this (the complete uncoating theory) is now doubted; rather the true picture is thought to be that capsid uncoating does indeed take place in the cytosol but that it is a process which takes place progressively as the [[capsid]] gets closer and closer to the nucleus, though the uncoating process usually, but not always, completes in the nucleus.<ref name="Science 370(6513)">{{cite journal | vauthors = Matreyek KA, Yücel SS, Li X, Engelman A | title = Nucleoporin NUP153 Phenylalanine-Glycine Motifs Engage a Common Binding Pocket within the HIV-1 Capsid Protein to Mediate Lentiviral Infectivity | journal = PLOS Pathogens| volume =   9| year = 2013| issue = 10| pages = e1003693| doi = 10.1371/journal.ppat.1003693 | pmid = 24130490 | pmc = 3795039 | doi-access = free }}</ref> Further, the viral genome in the capsid is reverse transcribed inside the viral capsid<ref name="pmid33033190">{{cite journal | vauthors = Christensen DE, Ganser-Pornillos BK, Johnson JS, Pornillos O, Sundquist WI | title = Reconstitution and visualization of HIV-1 capsid-dependent replication and integration in vitro. | journal = Science | volume = 370| pages = 1–11 | year = 2020 | issue = 6513 | pmid = 33033190 | doi = 10.1126/science.abc8420 | pmc = 6299210 }}</ref> to enable the production of daughter virions.
TRIM5α is a cytosolic protein that recognizes specific motifs on incoming viral [[capsid]]s. 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.<ref name="Fletcher_2018">{{cite journal | vauthors = Fletcher AJ, Vaysburd M, Maslen S, Zeng J, Skehel JM, Towers GJ, James LC | title = Trivalent RING Assembly on Retroviral Capsids Activates TRIM5 Ubiquitination and Innate Immune Signaling. | journal = Cell Host & Microbe | volume = 24 | issue = 6 | pages = 761–775.e6 | date = Dec 2018 | pmid = 30503508 | pmc = 6299210 | doi = 10.1016/j.chom.2018.10.007 }}</ref> 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.<ref name="Sebastian_2005">{{cite journal | vauthors = Sebastian S, Luban J | title = TRIM5alpha selectively binds a restriction-sensitive retroviral capsid | journal = Retrovirology | volume = 2 | pages = 40 | date = Jun 2005 | pmid = 15967037 | pmc = 1166576 | doi = 10.1186/1742-4690-2-40 | doi-access = free }}</ref><ref name="Stremlau_2006">{{cite journal | vauthors = 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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 14 | pages = 5514–5519 | date = Apr 2006 | pmid = 16540544 | pmc = 1459386 | doi = 10.1073/pnas.0509996103 | doi-access = free }}</ref>


TRIM5α is present in the cytosol. It recognizes motifs within viral [[capsid]] proteins, which causes the TRIM5α to smother the (not yet uncoated) viral [[capsid]] in a tessilatory manner so as to form a repeating regular hexagonal net, two sides of each hexagon being made up of two spokes of a three-way hub and spoke trimer<ref name="pmid30503508">{{cite journal | vauthors = Fletcher AJ, Vaysburd M, Maslen S, Zeng J, Skehel JM, Towers GJ, James LC | title = Trivalent RING Assembly on Retroviral Capsids Activates TRIM5 Ubiquitination and Innate Immune Signaling. | journal = Cell Host Microbe | volume = 24 | pages = 761–775.e6 | year = 2018 | issue = 6 | pmid = 30503508 | doi = 10.1016/j.chom.2018.10.007 | pmc = 6299210 }}</ref> and consequently by means of that smothering to interfere with any viral [[capsid]] uncoating process, thereby (1) preventing transport of the viral genome into the host cell nucleus and (2) also preventing successful reverse transcription of viral RNA into a length of DNA to be spliced into the host genome to enable expression of viral proteins via a transcrption process.<ref name="pmid15967037">{{cite journal | vauthors = Sebastian S, Luban J | title = TRIM5alpha selectively binds a restriction-sensitive retroviral capsid | journal = Retrovirology | volume = 2 | pages = 40 | year = 2005 | pmid = 15967037 | doi = 10.1186/1742-4690-2-40 | pmc = 1166576 | doi-access = free }}</ref><ref name="pmid16540544">{{cite journal | vauthors = 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 | pmc = 1459386 | doi-access = free }}</ref> The exact mechanism of action has not been shown conclusively, but capsid protein from restricted viruses (that is viruses which are the subject of TRIM5α intervention) is removed by [[proteasome]]-dependent degradation.<ref name="pmid16648264">{{cite journal | vauthors = 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 | pmc = 1464362 | bibcode = 2006PNAS..103.7465W | doi-access = free }}</ref> The TRIM5α, once formed into its highly regular reticulatory net recruits ubiquitin for this purpose, which, in turn engages the [[proteasome]].<ref name="pmid30503508"/>
While the full mechanism remains incompletely understood, it is known that TRIM5α promotes proteasome-dependent degradation of capsid proteins from restricted viruses.<ref name="Wu_2006">{{cite journal | vauthors = 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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 19 | pages = 7465–7470 | date = May 2006 | pmid = 16648264 | pmc = 1464362 | doi = 10.1073/pnas.0510483103 | bibcode = 2006PNAS..103.7465W | doi-access = free }}</ref> This process involves the recruitment of [[ubiquitin]] by the TRIM5α lattice, which subsequently targets the capsid for degradation by the [[proteasome]].<ref name="Fletcher_2018" />
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.<ref name="Berthoux_2005">{{cite journal | vauthors = 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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 41 | pages = 14849–14853 | date = Oct 2005 | pmid = 16203999 | pmc = 1239943 | doi = 10.1073/pnas.0505659102 | bibcode = 2005PNAS..10214849B | doi-access = free }}</ref>
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.<ref name="Ohkura_2006">{{cite journal | vauthors = 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 = Journal of Virology | volume = 80 | issue = 17 | pages = 8554–8565 | date = Sep 2006 | pmid = 16912305 | pmc = 1563890 | doi = 10.1128/JVI.00688-06 }}</ref> Within this domain, amino acid residue 332 plays a particularly important role in determining which retroviruses are restricted.<ref name="Yap_2005">{{cite journal | vauthors = 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 = Current Biology : CB | volume = 15 | issue = 1 | pages = 73–78 | date = Jan 2005 | pmid = 15649369 | doi = 10.1016/j.cub.2004.12.042 | s2cid = 1910582 | doi-access = free | bibcode = 2005CBio...15...73Y }}</ref><ref name="Kaiser_2007">{{cite journal | vauthors = Kaiser SM, Malik HS, Emerman M | title = Restriction of an extinct retrovirus by the human TRIM5alpha antiviral protein | journal = Science | location = New York, N.Y. | volume = 316 | issue = 5832 | pages = 1756–1758 | date = Jun 2007 | pmid = 17588933 | doi = 10.1126/science.1140579 | bibcode = 2007Sci...316.1756K | s2cid = 33225147 }}</ref>


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.<ref name="pmid16203999">{{cite journal | vauthors = 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 | pmc = 1239943 | bibcode = 2005PNAS..10214849B | doi-access = free }}</ref>
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.<ref name="Science 370(6513)">{{cite journal | vauthors = Matreyek KA, Yücel SS, Li X, Engelman A | title = Nucleoporin NUP153 Phenylalanine-Glycine Motifs Engage a Common Binding Pocket within the HIV-1 Capsid Protein to Mediate Lentiviral Infectivity | journal = PLOS Pathogens | volume = 9 | issue = 10 | pages = e1003693 | year = 2013 | pmid = 24130490 | pmc = 3795039 | doi = 10.1371/journal.ppat.1003693 | doi-access = free }}</ref> 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.<ref name="Christensen_2020">{{cite journal | vauthors = Christensen DE, Ganser-Pornillos BK, Johnson JS, Pornillos O, Sundquist WI | title = Reconstitution and visualization of HIV-1 capsid-dependent replication and integration in vitro. | journal = Science | location = New York, N.Y. | volume = 370 | issue = 6513 | pages = 1–11 | date = Oct 2020 | pmid = 33033190 | pmc = 6299210 | doi = 10.1126/science.abc8420 }}</ref>


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.<ref name="pmid16912305">{{cite journal | vauthors = 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 | pmc = 1563890 }}</ref> Amino acid 332, which occurs within this domain, seems to play a critical role in determining the specificity of retrovirus restriction.<ref name="pmid15649369">{{cite journal | vauthors = 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 | s2cid = 1910582 | doi-access = free | bibcode = 2005CBio...15...73Y }}</ref><ref name="pmid17588933">{{cite journal | vauthors = 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 | bibcode = 2007Sci...316.1756K | s2cid = 33225147 }}</ref>
== Clinical significance ==


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.<ref name="pmid17588933" /> 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.<ref name="pmid18927623">{{cite journal | vauthors = Perez-Caballero D, Soll SJ, [[Paul Bieniasz|Bieniasz PD]] | title = Evidence for restriction of ancient primate gammaretroviruses by APOBEC3 but not TRIM5alpha proteins | journal = PLOS Pathog.  | year = 2008 | pmid = 18927623 | doi=10.1371/journal.ppat.1000181 | volume = 4 | issue = 10 | pages = e1000181 | pmc = 2564838 | editor1-last = Hope | editor1-first = Thomas J. | doi-access = free }} {{open access}}</ref>
=== PtERV1 resistance ===


== Clinical significance ==
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.<ref name="Kaiser_2007" /> 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.<ref name="PerezCaballero_2008">{{cite journal | vauthors = Perez-Caballero D, Soll SJ, [[Paul Bieniasz | Bieniasz PD]] | title = Evidence for restriction of ancient primate gammaretroviruses by APOBEC3 but not TRIM5alpha proteins | journal = PLOS Pathogens | volume = 4 | issue = 10 | pages = e1000181 | date = Oct 2008 | pmid = 18927623 | pmc = 2564838 | doi = 10.1371/journal.ppat.1000181 | editor1-last = Hope | editor1-first = Thomas J. | doi-access = free }} {{open access}}</ref>
[[Rhesus macaque]]s, a species of [[Old World monkey]]s, appeared to be almost completely resistant to HIV-1, the virus that causes [[AIDS]] in humans.<ref>{{Cite journal|last1=Tenthorey|first1=Jeannette L|last2=Young|first2=Candice|last3=Sodeinde|first3=Afeez|last4=Emerman|first4=Michael|last5=Malik|first5=Harmit S|date=2020-09-15|editor-last=Schoggins|editor-first=John W|editor2-last=Weigel|editor2-first=Detlef|editor3-last=Berthoux|editor3-first=Lionel|title=Mutational resilience of antiviral restriction favors primate TRIM5α in host-virus evolutionary arms races|journal=eLife|volume=9|pages=e59988|doi=10.7554/eLife.59988|pmid=32930662|pmc=7492085|issn=2050-084X|doi-access=free}}</ref> The Rhesus macaques version of TRIM5α was very quick and had a high enough affinity to the incoming HIV capsule that it could bind and degrade it quickly so that the virus was neutralized.
 
=== HIV-1 resistance ===


Humans also have a TRIM5α, but it is not well enough tuned to mediate a sufficient response. However, the human version of TRIM5α can inhibit strains of the [[murine leukemia virus]] (MLV)<ref name="pmid15252204">{{cite journal | vauthors = 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 | pmc = 489964 | doi-access = free }}</ref><ref name="pmid15249690">{{cite journal | vauthors = 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 | pmc = 490012 | bibcode = 2004PNAS..10110786Y | doi-access = free }}</ref> as well as equine infectious anemia virus (EIAV).<ref name="pmid15249685">{{cite journal | vauthors = Hatziioannou T, Perez-Caballero D, Yang A, Cowan S, [[Paul Bieniasz|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 | pmc = 490010 | bibcode = 2004PNAS..10110774H | doi-access = free }}</ref><ref name="pmid15249687">{{cite journal | author1 = Keckesova Z |author-link1=Zuzana Kečkéšová |author2=Ylinen LM |author3=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 | pmc = 490011 | bibcode = 2004PNAS..10110780K |doi-access=free }}</ref>
[[Rhesus macaque]]s, a species of [[Old World monkey]]s, are almost completely resistant to HIV-1, the virus that causes [[AIDS]] in humans.<ref>{{Cite journal | vauthors = Tenthorey JL, Young C, Sodeinde A, Emerman M, Malik HS | title = Mutational resilience of antiviral restriction favors primate TRIM5α in host-virus evolutionary arms races | journal = eLife | volume = 9 | pages = e59988 | date = 2020-09-15 | pmid = 32930662 | pmc = 7492085 | doi = 10.7554/eLife.59988 | editor2-last = Weigel | editor2-first = Detlef | editor3-last = Berthoux | editor3-first = Lionel | issn = 2050-084X | doi-access = free | editor-first1 = John W | editor-last1 = Schoggins }}</ref> 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.


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.
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)<ref name="Lee_2004">{{cite journal | vauthors = Lee K, KewalRamani VN | title = In defense of the cell: TRIM5α interception of mammalian retroviruses | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 29 | pages = 10496–10497 | date = Jul 2004 | pmid = 15252204 | pmc = 489964 | doi = 10.1073/pnas.0404066101 | doi-access = free | bibcode = 2004PNAS..10110496L }}</ref><ref name="Yap_2004">{{cite journal | vauthors = Yap MW, Nisole S, Lynch C, Stoye JP | title = Trim5α protein restricts both HIV-1 and murine leukemia virus | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 29 | pages = 10786–10791 | date = Jul 2004 | pmid = 15249690 | pmc = 490012 | doi = 10.1073/pnas.0402876101 | bibcode = 2004PNAS..10110786Y | doi-access = free }}</ref> and equine infectious anemia virus (EIAV).<ref name="Hatziioannou_2004">{{cite journal | vauthors = Hatziioannou T, Perez-Caballero D, Yang A, Cowan S, [[Paul Bieniasz | Bieniasz PD]] | title = Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5α | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 29 | pages = 10774–10779 | date = Jul 2004 | pmid = 15249685 | pmc = 490010 | doi = 10.1073/pnas.0402361101 | bibcode = 2004PNAS..10110774H | doi-access = free }}</ref><ref name="Keckesova_2004">{{cite journal | vauthors = Keckesova Z, Ylinen LM, Towers GJ | title = The human and African green monkey TRIM5α genes encode Ref1 and Lv1 retroviral restriction factor activities | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 29 | pages = 10780–10785 | date = Jul 2004 | pmid = 15249687 | pmc = 490011 | doi = 10.1073/pnas.0402474101 | bibcode = 2004PNAS..10110780K | doi-access = free }}</ref>
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, named TRIMCyp (or TRIM5-CypA), was isolated in the [[owl monkey]], a species of [[New World monkey]], and shown to potently inhibit infection by HIV-1.<ref name="pmid15243629">{{cite journal | vauthors = 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 | bibcode = 2004Natur.430..569S | s2cid = 4379907 }}</ref> A similar protein has arisen independently in Old World monkeys and has been identified in several species of macaque.<ref name="pmid18287035">{{cite journal | vauthors = 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 | pmc = 2265179 | doi-access = free| bibcode = 2008PNAS..105.3557W}}</ref><ref name ="PMID18287033">{{cite journal | vauthors = Brennan G, Kozyrev Y, Hu SL | title = TRIMCyp expression in Old World primates Macaca nemestrina and Macaca fascicularis | journal = PNAS | volume = 105 | issue = 9 | pages = 3569–74 | year = 2008 | pmid = 18287033 | doi = 10.1073/pnas.0709511105 | pmc = 2265124| doi-access = free | bibcode = 2008PNAS..105.3569B }}</ref>
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.<ref name="Sayah_2004">{{cite journal | vauthors = 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 = 569–573 | date = Jul 2004 | pmid = 15243629 | doi = 10.1038/nature02777 | bibcode = 2004Natur.430..569S | s2cid = 4379907 }}</ref> A similar TRIMCyp protein has independently evolved in several species of Old World monkeys, including various macaques.<ref name="Wilson_2008">{{cite journal | vauthors = Wilson SJ, Webb BL, Ylinen LM, Verschoor E, Heeney JL, Towers GJ | title = Independent evolution of an antiviral TRIMCyp in rhesus macaques | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 9 | pages = 3557–3562 | date = Mar 2008 | pmid = 18287035 | pmc = 2265179 | doi = 10.1073/pnas.0709003105 | doi-access = free | bibcode = 2008PNAS..105.3557W }}</ref><ref name="Brennan_2008">{{cite journal | vauthors = Brennan G, Kozyrev Y, Hu SL | title = TRIMCyp expression in Old World primates Macaca nemestrina and Macaca fascicularis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 9 | pages = 3569–3574 | date = Mar 2008 | pmid = 18287033 | pmc = 2265124 | doi = 10.1073/pnas.0709511105 | doi-access = free | bibcode = 2008PNAS..105.3569B }}</ref>


It was recently described that interferon-α-mediated stimulation of the [[Proteasome|immunoproteasome]] enables human TRIM5α for effective capsid-dependent inhibition of HIV-1 DNA synthesis and infection.<ref>{{Cite journal|last1=Malim|first1=Michael H.|last2=Gilberto Betancor|last3=Apolonia|first3=Luis|last4=Jimenez-Guardeño|first4=Jose M.|date=2019-03-18|title=Immunoproteasome activation enables human TRIM5α restriction of HIV-1|journal=Nature Microbiology|volume=4|issue=6|language=en|pages=933–940|doi=10.1038/s41564-019-0402-0|pmid=30886358|pmc=6544544|issn=2058-5276}}</ref>
More recently, it has been shown that stimulation with interferon-α can activate the [[Proteasome|immunoproteasome]], enabling human TRIM5α to effectively block HIV-1 by interfering with capsid-dependent DNA synthesis and infection.<ref>{{cite journal | vauthors = Jimenez-Guardeño JM, Apolonia L, Betancor G, Malim MH | title = Immunoproteasome activation enables human TRIM5α restriction of HIV-1 | journal = Nature Microbiology | volume = 4 | issue = 6 | pages = 933–940 | date = June 2019 | pmid = 30886358 | pmc = 6544544 | doi = 10.1038/s41564-019-0402-0 }}</ref>


== Notes and references ==
== Notes and references ==
Line 35: Line 40:


== External links==
== External links==
* {{cite web | url = http://www.expasy.org/cgi-bin/niceprot.pl?Q6BC81 | title = UniProtKB/Swiss-Prot entry Q587N7 (TRIM5_CERAE) Tripartite motif-containing protein 5 | access-date = 2008-02-19 | publisher = [[Swiss Institute of Bioinformatics]] }}
* {{cite web | title = UniProtKB/Swiss-Prot entry Q587N7 (TRIM5_CERAE) Tripartite motif-containing protein 5 | url = http://www.expasy.org/cgi-bin/niceprot.pl?Q6BC81 | access-date = 2008-02-19 | publisher = [[Swiss Institute of Bioinformatics]] }}
* {{cite web | url = https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=48994821 | title = NCBI Sequence Viewer v2.0 | access-date = 2008-02-19 | publisher = National Center for Biotechnology Information }}
* {{cite web | title = NCBI Sequence Viewer v2.0 | url = https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=48994821 | access-date = 2008-02-19 | publisher = National Center for Biotechnology Information }}
* {{cite web | url = http://www.sciam.com/article.cfm?articleid=4EFE4EBA-E7F2-99DF-357CBEBCDDDE6884 | title = Defense against Ancient Virus Opened Door to HIV | access-date = 2008-02-19 | author = Minkel JR| date = 2007-06-21| work = Scientific American }}
* {{cite web | vauthors = Minkel JR | title = Defense against Ancient Virus Opened Door to HIV | date = 2007-06-21 | url = http://www.sciam.com/article.cfm?articleid=4EFE4EBA-E7F2-99DF-357CBEBCDDDE6884 | access-date = 2008-02-19 | work = Scientific American }}
* {{cite journal | url = http://www.nature.com/news/2007/070618/full/070618-15.html | title = Access : Ancient disease resistance made us vulnerable to HIV | access-date = 2008-02-19 | author = Hopkin M | date = 2007-06-26 | journal = Nature News | doi = 10.1038/news070618-15 | s2cid = 84816126 | url-access = subscription }}
* {{cite journal | vauthors = Hopkin M | title = Access : Ancient disease resistance made us vulnerable to HIV | journal = Nature News | date = 2007-06-26 | doi = 10.1038/news070618-15 | url = http://www.nature.com/news/2007/070618/full/070618-15.html | access-date = 2008-02-19 | s2cid = 84816126 | url-access = subscription }}
* {{PDBe-KB2|Q9C035|Tripartite motif-containing protein 5}}
* {{PDBe-KB2|Q9C035|Tripartite motif-containing protein 5}}


Latest revision as of 08:55, 24 June 2025

Template:Cs1 config Template:Infobox gene 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

Template:Reflist

External links

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See also

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  22. ↑ Script error: No such module "Citation/CS1".
  23. ↑ Script error: No such module "Citation/CS1".
  24. ↑ Script error: No such module "Citation/CS1".
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