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TRIM5 and the Regulation of HIV-1 Infectivity.

Luban J - Mol Biol Int (2012)

Bottom Line: Unattached, K63-linked ubiquitin chains are generated that activate the TAK1 kinase complex and downstream inflammatory mediators.Polymorphisms in the capsid recognition domain of TRIM5 explain the observed species-specific differences among orthologues and the relatively weak anti-HIV-1 activity of human TRIM5.Better understanding of the complex interaction between TRIM5 and the retrovirus capsid lattice may someday lead to exploitation of this interaction for the development of potent HIV-1 inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Medicine, University of Geneva, 1211 Geneva, Switzerland.

ABSTRACT
The past ten years have seen an explosion of information concerning host restriction factors that inhibit the replication of HIV-1 and other retroviruses. Among these factors is TRIM5, an innate immune signaling molecule that recognizes the capsid lattice as soon as the retrovirion core is released into the cytoplasm of otherwise susceptible target cells. Recognition of the capsid lattice has several consequences that include multimerization of TRIM5 into a complementary lattice, premature uncoating of the virion core, and activation of TRIM5 E3 ubiquitin ligase activity. Unattached, K63-linked ubiquitin chains are generated that activate the TAK1 kinase complex and downstream inflammatory mediators. Polymorphisms in the capsid recognition domain of TRIM5 explain the observed species-specific differences among orthologues and the relatively weak anti-HIV-1 activity of human TRIM5. Better understanding of the complex interaction between TRIM5 and the retrovirus capsid lattice may someday lead to exploitation of this interaction for the development of potent HIV-1 inhibitors.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram showing current models of TRIM5-mediated restriction. Free TRIM5 probably exists as a dimer in the target cell cytoplasm. Upon interaction with the capsid of a restriction-sensitive retrovirus, the propensity of TRIM5 to form a complementary hexameric lattice is stimulated. This increases its intrinsic E3 ubiquitin ligase activity. If avidity for the retrovirus capsid is sufficient, the virion core prematurely uncoats and reverse transcription is blocked. Depending upon the proximity of particular cellular E2 enzymes, TRIM5 will either autoubiquitinate and traffic towards proteasomes, or it will activate the TAK1 kinase and downstream signaling molecules.
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fig1: Schematic diagram showing current models of TRIM5-mediated restriction. Free TRIM5 probably exists as a dimer in the target cell cytoplasm. Upon interaction with the capsid of a restriction-sensitive retrovirus, the propensity of TRIM5 to form a complementary hexameric lattice is stimulated. This increases its intrinsic E3 ubiquitin ligase activity. If avidity for the retrovirus capsid is sufficient, the virion core prematurely uncoats and reverse transcription is blocked. Depending upon the proximity of particular cellular E2 enzymes, TRIM5 will either autoubiquitinate and traffic towards proteasomes, or it will activate the TAK1 kinase and downstream signaling molecules.

Mentions: One of the biggest ongoing challenges for researchers studying TRIM5 is to understand the structural basis for CA recognition. TRIM5 is a multimer, and CA recognition does not occur via a simple protein-protein interaction. Rather, TRIM5 recognizes a complex surface involving the CA lattice [58, 59]. In fact, TRIM5 spontaneously forms a hexameric protein lattice, and this propensity to form a lattice is greatly stimulated in the presence of the CA lattice [60] (Figure 1). This explains why a simple binding assay has not been developed. Extensive efforts have been made by several groups to develop soluble subdomains of the CA lattice that might be used in binding studies [61, 62]. The soluble hexamer unit, for example, seems not to bind to TRIM5 [63, 64]. In contrast, promising results have been obtained with a CA trimer [64]. A requirement for additional host factors such as SUMO-1 may complicate the situation with CA recognition even further [65].


TRIM5 and the Regulation of HIV-1 Infectivity.

Luban J - Mol Biol Int (2012)

Schematic diagram showing current models of TRIM5-mediated restriction. Free TRIM5 probably exists as a dimer in the target cell cytoplasm. Upon interaction with the capsid of a restriction-sensitive retrovirus, the propensity of TRIM5 to form a complementary hexameric lattice is stimulated. This increases its intrinsic E3 ubiquitin ligase activity. If avidity for the retrovirus capsid is sufficient, the virion core prematurely uncoats and reverse transcription is blocked. Depending upon the proximity of particular cellular E2 enzymes, TRIM5 will either autoubiquitinate and traffic towards proteasomes, or it will activate the TAK1 kinase and downstream signaling molecules.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369500&req=5

fig1: Schematic diagram showing current models of TRIM5-mediated restriction. Free TRIM5 probably exists as a dimer in the target cell cytoplasm. Upon interaction with the capsid of a restriction-sensitive retrovirus, the propensity of TRIM5 to form a complementary hexameric lattice is stimulated. This increases its intrinsic E3 ubiquitin ligase activity. If avidity for the retrovirus capsid is sufficient, the virion core prematurely uncoats and reverse transcription is blocked. Depending upon the proximity of particular cellular E2 enzymes, TRIM5 will either autoubiquitinate and traffic towards proteasomes, or it will activate the TAK1 kinase and downstream signaling molecules.
Mentions: One of the biggest ongoing challenges for researchers studying TRIM5 is to understand the structural basis for CA recognition. TRIM5 is a multimer, and CA recognition does not occur via a simple protein-protein interaction. Rather, TRIM5 recognizes a complex surface involving the CA lattice [58, 59]. In fact, TRIM5 spontaneously forms a hexameric protein lattice, and this propensity to form a lattice is greatly stimulated in the presence of the CA lattice [60] (Figure 1). This explains why a simple binding assay has not been developed. Extensive efforts have been made by several groups to develop soluble subdomains of the CA lattice that might be used in binding studies [61, 62]. The soluble hexamer unit, for example, seems not to bind to TRIM5 [63, 64]. In contrast, promising results have been obtained with a CA trimer [64]. A requirement for additional host factors such as SUMO-1 may complicate the situation with CA recognition even further [65].

Bottom Line: Unattached, K63-linked ubiquitin chains are generated that activate the TAK1 kinase complex and downstream inflammatory mediators.Polymorphisms in the capsid recognition domain of TRIM5 explain the observed species-specific differences among orthologues and the relatively weak anti-HIV-1 activity of human TRIM5.Better understanding of the complex interaction between TRIM5 and the retrovirus capsid lattice may someday lead to exploitation of this interaction for the development of potent HIV-1 inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Medicine, University of Geneva, 1211 Geneva, Switzerland.

ABSTRACT
The past ten years have seen an explosion of information concerning host restriction factors that inhibit the replication of HIV-1 and other retroviruses. Among these factors is TRIM5, an innate immune signaling molecule that recognizes the capsid lattice as soon as the retrovirion core is released into the cytoplasm of otherwise susceptible target cells. Recognition of the capsid lattice has several consequences that include multimerization of TRIM5 into a complementary lattice, premature uncoating of the virion core, and activation of TRIM5 E3 ubiquitin ligase activity. Unattached, K63-linked ubiquitin chains are generated that activate the TAK1 kinase complex and downstream inflammatory mediators. Polymorphisms in the capsid recognition domain of TRIM5 explain the observed species-specific differences among orthologues and the relatively weak anti-HIV-1 activity of human TRIM5. Better understanding of the complex interaction between TRIM5 and the retrovirus capsid lattice may someday lead to exploitation of this interaction for the development of potent HIV-1 inhibitors.

No MeSH data available.


Related in: MedlinePlus