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TRIM5 is an innate immune sensor for the retrovirus capsid lattice.
Nature. 2011 Apr 21; 472(7343):361-5
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11 May 2011
Confirmation, New Finding
DOI: 10.3410/f.10103964.10867065
This study demonstrates the long suspected E3 ubiquitin ligase activity of TRIM5 and its role in eliciting a proinflammatory response to retroviral capsids, thus acting as a pattern recognition receptor. In addition, one of its products, the 'unattached' tetra-ubiquitin chain, seems to act as a second...Continue reading
This study demonstrates the long suspected E3 ubiquitin ligase activity of TRIM5 and its role in eliciting a proinflammatory response to retroviral capsids, thus acting as a pattern recognition receptor. In addition, one of its products, the 'unattached' tetra-ubiquitin chain, seems to act as a second messenger to activate proinflammatory signaling through nuclear factor-kappaB (NF-kB). Definitely a very interesting and well done paper.
TRIM5 is one of the key anti-retroviral cell-autonomous restriction factors, which, in the case of HIV-1, unfortunately has low potency in humans but is very good at restricting HIV-1 in several monkey species. The loss is due to a drift or other virus-directed changes in HIV-1 recognition sites within TRIM5's SPRY domain. It is not known how TRIM5 works, although it seems to restrict infection by interfering with the incoming viral core by recognizing the viral capsid lattice. This particular study has linked, in a very thorough and elegant way, the (previously suspected) E3 ligase activity of TRIM5 with proinflammatory signaling via a new second messenger (the 'unattached' tetra-K63-ubiquitin chains) to TAK1 and downstream NF-kB activation. Yet, the effector mechanism that intercepts the incoming HIV after, prior or concomitant with the activation remains to be identified. The search is on!
It should be noted that a reader relatively uninitiated in the field of TRIM-ology should consult an excellent review on TRIM proteins {1}, considering the fact that human TRIM5 is not really good at restricting HIV-1. This issue has not been covered in the study. The reader can consult the references cited below {2-7}, among others.
References:
{1} Ozato et al. Nat Rev Immunol 2008, 8:849-60 [PMID:18836477].
{2} Stremlau et al. Nature 2004, 427:848-53 [PMID:14985764].
{3} Keckesova et al. Proc Natl Acad Sci U S A 2004, 101:10780-5 [PMID:15249687].
{4} Yap et al. Proc Natl Acad Sci U S A 2004, 101:10786-91 [PMID:15249690].
{5} Sakuma et al. Nat Med 2007, 13:631-5 [PMID:17435772].
{6} Campbell et al. J Cell Biol 2008, 180:549-61 [PMID:18250195].
{7} Johnson and Sawyer, Immunogenetics 2009, 61:163-76 [PMID:19238338].
TRIM5 is one of the key anti-retroviral cell-autonomous restriction factors, which, in the case of HIV-1, unfortunately has low potency in humans but is very good at restricting HIV-1 in several monkey species. The loss is due to a drift or other virus-directed changes in HIV-1 recognition sites within TRIM5's SPRY domain. It is not known how TRIM5 works, although it seems to restrict infection by interfering with the incoming viral core by recognizing the viral capsid lattice. This particular study has linked, in a very thorough and elegant way, the (previously suspected) E3 ligase activity of TRIM5 with proinflammatory signaling via a new second messenger (the 'unattached' tetra-K63-ubiquitin chains) to TAK1 and downstream NF-kB activation. Yet, the effector mechanism that intercepts the incoming HIV after, prior or concomitant with the activation remains to be identified. The search is on!
It should be noted that a reader relatively uninitiated in the field of TRIM-ology should consult an excellent review on TRIM proteins {1}, considering the fact that human TRIM5 is not really good at restricting HIV-1. This issue has not been covered in the study. The reader can consult the references cited below {2-7}, among others.
References:
{1} Ozato et al. Nat Rev Immunol 2008, 8:849-60 [PMID:18836477].
{2} Stremlau et al. Nature 2004, 427:848-53 [PMID:14985764].
{3} Keckesova et al. Proc Natl Acad Sci U S A 2004, 101:10780-5 [PMID:15249687].
{4} Yap et al. Proc Natl Acad Sci U S A 2004, 101:10786-91 [PMID:15249690].
{5} Sakuma et al. Nat Med 2007, 13:631-5 [PMID:17435772].
{6} Campbell et al. J Cell Biol 2008, 180:549-61 [PMID:18250195].
{7} Johnson and Sawyer, Immunogenetics 2009, 61:163-76 [PMID:19238338].
Disclosures
None declared
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Deretic V: F1000Prime Recommendation of [Pertel T et al., Nature 2011, 472(7343):361-5]. In F1000Prime, 11 May 2011; DOI: 10.3410/f.10103964.10867065. F1000Prime.com/10103964#eval10867065
23 May 2011
New Finding
DOI: 10.3410/f.10103964.11558054
Several tri-partite motif (TRIM) proteins have previously been shown to modulate innate immunity or to function as viral restrictions factors. This paper puts forward the interesting finding that TRIM5, previously shown to directly restrict HIV, may also act as a bona fide pattern restriction receptor...Continue reading
Several tri-partite motif (TRIM) proteins have previously been shown to modulate innate immunity or to function as viral restrictions factors. This paper puts forward the interesting finding that TRIM5, previously shown to directly restrict HIV, may also act as a bona fide pattern restriction receptor (PRR) and recognize retroviral capsids. Moreover, the authors show that TRIM5 mediates signaling, ultimately activating the nuclear factor kappa B (NFkB) pathway. Together, these findings add TRIM5 to a growing list of TRIMs that regulate innate immune responses. It raises the question if more of the nearly eighty TRIM family members have evolved to function as PRRs and enhance innate immune signaling.
Using knock-down studies, the authors demonstrate that TRIM5 enhances NFkB signaling by activating the TAK1/TAB2/TAB3 complex. Further in vitro experiments with purified TRIM5 suggest that TRIM5 facilitates the synthesis of linear Lys63-linked free ubiquitin chains that can subsequently activate the TAK1 kinase complex. Finally, studies with viruses expressing TRIM5-restricted or unrestricted capsids and experiments with isolated capsid cylinders indicate direct recognition of the retrovirus capsid lattice by TRIM5 as a PRR, subsequently engaging innate immune signaling. These findings bring up the question if other TRIMs that have recently arisen in evolution share this ability. It could indicate that the plethora of PRRs and innate immune modulators is more complex than hitherto anticipated.
Using knock-down studies, the authors demonstrate that TRIM5 enhances NFkB signaling by activating the TAK1/TAB2/TAB3 complex. Further in vitro experiments with purified TRIM5 suggest that TRIM5 facilitates the synthesis of linear Lys63-linked free ubiquitin chains that can subsequently activate the TAK1 kinase complex. Finally, studies with viruses expressing TRIM5-restricted or unrestricted capsids and experiments with isolated capsid cylinders indicate direct recognition of the retrovirus capsid lattice by TRIM5 as a PRR, subsequently engaging innate immune signaling. These findings bring up the question if other TRIMs that have recently arisen in evolution share this ability. It could indicate that the plethora of PRRs and innate immune modulators is more complex than hitherto anticipated.
Disclosures
None declared
Garcia-Sastre A and Versteeg G: F1000Prime Recommendation of [Pertel T et al., Nature 2011, 472(7343):361-5]. In F1000Prime, 23 May 2011; DOI: 10.3410/f.10103964.11558054. F1000Prime.com/10103964#eval11558054
23 May 2011
Confirmation, New Finding
DOI: 10.3410/f.10103964.11467054
This study first shows that TRIM5 constitutively participates in innate immune signaling, which is greatly enhanced by interaction with retroviral capsids. TRIM5 synthesizes K63-linked polyubiquitin chains that activate the TAK1 kinase complex and its consequent signaling cascade.
It has long been...Continue reading
It has long been...Continue reading
This study first shows that TRIM5 constitutively participates in innate immune signaling, which is greatly enhanced by interaction with retroviral capsids. TRIM5 synthesizes K63-linked polyubiquitin chains that activate the TAK1 kinase complex and its consequent signaling cascade.
It has long been known that TRIM5 restricts retroviral infection by destablizing viral capsids. This antiviral activity depends on the C-terminal capsid-interacting SPRY domain. On its N-terminus, TRIM5 contains a RING domain, indicating E3 ligase activity. In this study, Pertel et. al. first demonstrate that TRIM5 stimulates nuclear factor kappa B (NF-kappaB) and AP-1 signaling pathways, using overexpression and knockdown methods. This information prompts the authors to examine 20 signaling proteins for their interaction with TRIM5, notably among them is the TAK1 kinase complex.
AP-1 stimulation by TRIM5 depends on the integrity of its N-terminal RING domain. The authors find TRIM5 working with heterodimeric E2 Ubc13/Uev1A to generate K63-linked free polyubiquitin chains that recruit and activate the TAK1 complex. Using purified recombinant TRIM5Cyp and other relevant proteins, Pertel et. al. reconstitute the ubiquitination processes in vitro, which in itself is a great deed.
More excitingly, encounter with viral capsids enhances both polyubiquitin formation and NF-kappaB signaling. This functionally links the domains of TRIM5 and makes TRIM5 a de novo pattern recognition receptor (PRR).
It has long been known that TRIM5 restricts retroviral infection by destablizing viral capsids. This antiviral activity depends on the C-terminal capsid-interacting SPRY domain. On its N-terminus, TRIM5 contains a RING domain, indicating E3 ligase activity. In this study, Pertel et. al. first demonstrate that TRIM5 stimulates nuclear factor kappa B (NF-kappaB) and AP-1 signaling pathways, using overexpression and knockdown methods. This information prompts the authors to examine 20 signaling proteins for their interaction with TRIM5, notably among them is the TAK1 kinase complex.
AP-1 stimulation by TRIM5 depends on the integrity of its N-terminal RING domain. The authors find TRIM5 working with heterodimeric E2 Ubc13/Uev1A to generate K63-linked free polyubiquitin chains that recruit and activate the TAK1 complex. Using purified recombinant TRIM5Cyp and other relevant proteins, Pertel et. al. reconstitute the ubiquitination processes in vitro, which in itself is a great deed.
More excitingly, encounter with viral capsids enhances both polyubiquitin formation and NF-kappaB signaling. This functionally links the domains of TRIM5 and makes TRIM5 a de novo pattern recognition receptor (PRR).
Disclosures
None declared
Wu H and Yin Q: F1000Prime Recommendation of [Pertel T et al., Nature 2011, 472(7343):361-5]. In F1000Prime, 23 May 2011; DOI: 10.3410/f.10103964.11467054. F1000Prime.com/10103964#eval11467054
10 Jun 2011
Shizuo Akira
F1000 Immunology
World Premier International Immunology Frontier Research Center, Osaka University,
Osaka, Japan.
F1000 Immunology
World Premier International Immunology Frontier Research Center, Osaka University,
Osaka, Japan.
New Finding
DOI: 10.3410/f.10103964.11952054
This study demonstrates that tripartite motif 5 (TRIM5) functions as a pattern-recognition receptor that triggers innate immune signaling pathways via recognition of retroviral capsids and gives insights into the mechanism by which TRIM5 restricts HIV infection.
TRIM5 is well known to restrict infection...Continue reading
TRIM5 is well known to restrict infection...Continue reading
This study demonstrates that tripartite motif 5 (TRIM5) functions as a pattern-recognition receptor that triggers innate immune signaling pathways via recognition of retroviral capsids and gives insights into the mechanism by which TRIM5 restricts HIV infection.
TRIM5 is well known to restrict infection of HIV-1 by binding to the viral capsid and causing premature capsid disassembly. Here, the authors find that overexpression of human TRIM5 results in enhancement of nuclear factor-kappa B (NF-kB)- and AP-1-driven gene expression, whereas its knockdown decreases the expression of NF-kB- and AP1-dependent proinflammatory genes. TRIM5 binds to the kinase complex involving TAK1, TAB2 and TAB3, and E2 ubiquitin conjugation enzymes UBC13 and UEV1A that promote the synthesis of Lys63-linked unattached ubiquitin chains. This results in the activation of TAK1 and subsequent induction of the expression of NF-kB- and AP1-dependent genes. Notably, in vitro experiments indicate that engagement of TRIM5 by the HIV-1 capsid lattice enhances TRIM5 E3 ubiquitin ligase activity. Thus, TRIM5 acts as a pattern-recognition receptor that recognizes the retrovirus capsid and elicits proinflammatory signaling pathways.
TRIM5 is well known to restrict infection of HIV-1 by binding to the viral capsid and causing premature capsid disassembly. Here, the authors find that overexpression of human TRIM5 results in enhancement of nuclear factor-kappa B (NF-kB)- and AP-1-driven gene expression, whereas its knockdown decreases the expression of NF-kB- and AP1-dependent proinflammatory genes. TRIM5 binds to the kinase complex involving TAK1, TAB2 and TAB3, and E2 ubiquitin conjugation enzymes UBC13 and UEV1A that promote the synthesis of Lys63-linked unattached ubiquitin chains. This results in the activation of TAK1 and subsequent induction of the expression of NF-kB- and AP1-dependent genes. Notably, in vitro experiments indicate that engagement of TRIM5 by the HIV-1 capsid lattice enhances TRIM5 E3 ubiquitin ligase activity. Thus, TRIM5 acts as a pattern-recognition receptor that recognizes the retrovirus capsid and elicits proinflammatory signaling pathways.
Disclosures
None declared
Akira S and Kawai T: F1000Prime Recommendation of [Pertel T et al., Nature 2011, 472(7343):361-5]. In F1000Prime, 10 Jun 2011; DOI: 10.3410/f.10103964.11952054. F1000Prime.com/10103964#eval11952054
F1000Prime Recommendations, Dissents and Comments for [Pertel T et al., Nature 2011, 472(7343):361-5]. In F1000Prime, 22 May 2013; F1000Prime.com/10103964
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TRIM5 is a RING domain-E3 ubiquitin ligase that restricts infection by human immunodeficiency virus (HIV)-1 and other retroviruses immediately following virus invasion of the target cell cytoplasm. Antiviral potency correlates with TRIM5 avidity for the retrovirion capsid lattice and several reports indicate that TRIM5 has a role in signal transduction, but the precise mechanism of restriction is unknown. Here we demonstrate that TRIM5 promotes innate immune signalling and that this activity is amplified by retroviral infection and interaction with the capsid lattice. Acting with the heterodimeric, ubiquitin-conjugating enzyme UBC13-UEV1A (also known as UBE2N-UBE2V1), TRIM5 catalyses the synthesis of unattached K63-linked ubiquitin chains that activate the TAK1 (also known as MAP3K7) kinase complex and stimulate AP-1 and NFκB signalling. Interaction with the HIV-1 capsid lattice greatly enhances the UBC13-UEV1A-dependent E3 activity of TRIM5 and challenge with retroviruses induces the transcription of AP-1 and NF-κB-dependent factors with a magnitude that tracks with TRIM5 avidity for the invading capsid. Finally, TAK1 and UBC13-UEV1A contribute to capsid-specific restriction by TRIM5. Thus, the retroviral restriction factor TRIM5 has two additional activities that are linked to restriction: it constitutively promotes innate immune signalling and it acts as a pattern recognition receptor specific for the retrovirus capsid lattice.
DOI: 10.1038/nature09976
PMID: 21512573
