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COP9 signalosome component JAB1/CSN5 is necessary for T cell signaling through LFA-1 and HIV-1 replication.

Kinoshita SM, Krutzik PO, Nolan GP - PLoS ONE (2012)

Bottom Line: To determine critical host factors involved in HIV-1 replication, a dominant effector genetics approach was developed to reveal signaling pathways on which HIV-1 depends for replication.JAB1 expression overcame the inhibition of HIV-1 replication in the presence of peptide and also promoted HIV-1 replication in activated primary CD4(+) T cells.Thus, genetic selection for intracellular aptamer inhibitors of host cell processes proximal to signals at the immunological synapse of T cells can define unique mechanisms important to HIV-1 replication.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immune Regulation, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka, Japan. shigemik@biken.osaka-u.ac.jp

ABSTRACT
To determine critical host factors involved in HIV-1 replication, a dominant effector genetics approach was developed to reveal signaling pathways on which HIV-1 depends for replication. A large library of short peptide aptamers was expressed via retroviral delivery in T cells. Peptides that interfered with T cell activation-dependent processes that might support HIV-1 replication were identified. One of the selected peptides altered signaling, lead to a difference in T cell activation status, and inhibited HIV-1 replication. The target of the peptide was JAB1/CSN5, a component of the signalosome complex. JAB1 expression overcame the inhibition of HIV-1 replication in the presence of peptide and also promoted HIV-1 replication in activated primary CD4(+) T cells. This peptide blocked physiological release of JAB1 from the accessory T cell surface protein LFA-1, downstream AP-1 dependent events, NFAT activation, and HIV-1 replication. Thus, genetic selection for intracellular aptamer inhibitors of host cell processes proximal to signals at the immunological synapse of T cells can define unique mechanisms important to HIV-1 replication.

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Proposed model for the inhibition of signalling pathway by Pep24.(A) After LFA-1 activation, JAB1 relocalizes into cytoplasm and nucleus, activates AP-1 and induces gene activation, and finally activates HIV-1 replication. (B) When Pep24 binds to JAB-1, JAB1 relocalization is blocked inhibiting downstream signals and HIV-1 replication.
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pone-0041725-g008: Proposed model for the inhibition of signalling pathway by Pep24.(A) After LFA-1 activation, JAB1 relocalizes into cytoplasm and nucleus, activates AP-1 and induces gene activation, and finally activates HIV-1 replication. (B) When Pep24 binds to JAB-1, JAB1 relocalization is blocked inhibiting downstream signals and HIV-1 replication.

Mentions: The peptide, Pep24, was selected from a peptide library in a dominant effector genetics approach for its ability to represses host pathways that are important for HIV-1 replication in T cells. Pep24 was used as ‘bait’ to identify the host factor JAB1 as an important component that regulates HIV-1 replication in T cells. JAB1 (also known as CSN5) is involved in the activation of c-Jun, a component of the AP-1 heterodimeric transcription factor [28]. Pep24 inhibited relocalization of JAB1 post-LFA-1 engagement, downstream signaling pathways, and, therefore, HIV-1 replication (Figure 8). As JAB1 enhanced HIV-1 replication only in PHA-activated primary CD4+ T cells, JAB1 is a mediator of HIV-1 replication only after appropriate signaling primes its activity.


COP9 signalosome component JAB1/CSN5 is necessary for T cell signaling through LFA-1 and HIV-1 replication.

Kinoshita SM, Krutzik PO, Nolan GP - PLoS ONE (2012)

Proposed model for the inhibition of signalling pathway by Pep24.(A) After LFA-1 activation, JAB1 relocalizes into cytoplasm and nucleus, activates AP-1 and induces gene activation, and finally activates HIV-1 replication. (B) When Pep24 binds to JAB-1, JAB1 relocalization is blocked inhibiting downstream signals and HIV-1 replication.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3404009&req=5

pone-0041725-g008: Proposed model for the inhibition of signalling pathway by Pep24.(A) After LFA-1 activation, JAB1 relocalizes into cytoplasm and nucleus, activates AP-1 and induces gene activation, and finally activates HIV-1 replication. (B) When Pep24 binds to JAB-1, JAB1 relocalization is blocked inhibiting downstream signals and HIV-1 replication.
Mentions: The peptide, Pep24, was selected from a peptide library in a dominant effector genetics approach for its ability to represses host pathways that are important for HIV-1 replication in T cells. Pep24 was used as ‘bait’ to identify the host factor JAB1 as an important component that regulates HIV-1 replication in T cells. JAB1 (also known as CSN5) is involved in the activation of c-Jun, a component of the AP-1 heterodimeric transcription factor [28]. Pep24 inhibited relocalization of JAB1 post-LFA-1 engagement, downstream signaling pathways, and, therefore, HIV-1 replication (Figure 8). As JAB1 enhanced HIV-1 replication only in PHA-activated primary CD4+ T cells, JAB1 is a mediator of HIV-1 replication only after appropriate signaling primes its activity.

Bottom Line: To determine critical host factors involved in HIV-1 replication, a dominant effector genetics approach was developed to reveal signaling pathways on which HIV-1 depends for replication.JAB1 expression overcame the inhibition of HIV-1 replication in the presence of peptide and also promoted HIV-1 replication in activated primary CD4(+) T cells.Thus, genetic selection for intracellular aptamer inhibitors of host cell processes proximal to signals at the immunological synapse of T cells can define unique mechanisms important to HIV-1 replication.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immune Regulation, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka, Japan. shigemik@biken.osaka-u.ac.jp

ABSTRACT
To determine critical host factors involved in HIV-1 replication, a dominant effector genetics approach was developed to reveal signaling pathways on which HIV-1 depends for replication. A large library of short peptide aptamers was expressed via retroviral delivery in T cells. Peptides that interfered with T cell activation-dependent processes that might support HIV-1 replication were identified. One of the selected peptides altered signaling, lead to a difference in T cell activation status, and inhibited HIV-1 replication. The target of the peptide was JAB1/CSN5, a component of the signalosome complex. JAB1 expression overcame the inhibition of HIV-1 replication in the presence of peptide and also promoted HIV-1 replication in activated primary CD4(+) T cells. This peptide blocked physiological release of JAB1 from the accessory T cell surface protein LFA-1, downstream AP-1 dependent events, NFAT activation, and HIV-1 replication. Thus, genetic selection for intracellular aptamer inhibitors of host cell processes proximal to signals at the immunological synapse of T cells can define unique mechanisms important to HIV-1 replication.

Show MeSH
Related in: MedlinePlus