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TRAF5 is a downstream target of MAVS in antiviral innate immune signaling.

Tang ED, Wang CY - PLoS ONE (2010)

Bottom Line: The recognition of nucleic acids by the innate immune system during viral infection results in the production of type I interferons and the activation of antiviral immune responses.Alternatively, the activation of NF-kappaB leads to proinflammatory cytokine production.However, TRAF3-deficient cells display only a partial reduction in interferon production in response to RNA virus infection and are not defective in NF-kappaB activation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Signalling, Division of Oral Biology and Medicine, University of California Los Angeles School of Dentistry, Los Angeles, California, United States of America.

ABSTRACT
The recognition of nucleic acids by the innate immune system during viral infection results in the production of type I interferons and the activation of antiviral immune responses. The RNA helicases RIG-I and MDA-5 recognize distinct types of cytosolic RNA species and signal through the mitochondrial protein MAVS to stimulate the phosphorylation and activation of the transcription factors IRF3 and IRF7, thereby inducing type I interferon expression. Alternatively, the activation of NF-kappaB leads to proinflammatory cytokine production. The function of MAVS is dependent on both its C-terminal transmembrane (TM) domain and N-terminal caspase recruitment domain (CARD). The TM domain mediates MAVS dimerization in response to viral RNA, allowing the CARD to bind to and activate the downstream effector TRAF3. Notably, dimerization of the MAVS CARD alone is sufficient to activate IRF3, IRF7, and NF-kappaB. However, TRAF3-deficient cells display only a partial reduction in interferon production in response to RNA virus infection and are not defective in NF-kappaB activation. Here we find that the related ubiquitin ligase TRAF5 is a downstream target of MAVS that mediates both IRF3 and NF-kappaB activation. The TM domain of MAVS allows it to dimerize and thereby associate with TRAF5 and induce its ubiquitination in a CARD-dependent manner. Also, NEMO is recruited to the dimerized MAVS CARD domain in a TRAF3 and TRAF5-dependent manner. Thus, our findings reveal a possible function for TRAF5 in mediating the activation of IRF3 and NF-kappaB downstream of MAVS through the recruitment of NEMO. TRAF5 may be a key molecule in the innate response against viral infection.

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Schematic representation of model for signal transduction downstream of MAVS.MAVS homodimers, induced by binding of the activated forms of the RLRs RIG-I and MDA-5, are able to signal downstream in a TRAF3 and TRAF5-dependent manner to activate IRF3/7 and in a TRAF5-dependent manner to activate NF-κB. NEMO may be recruited to the MAVS signaling complex by ubiquitinated TRAF3 and TRAF5, and may lead to IRF3 phosphorylation through the recruitment of TANK and TBK1. Alternatively, NEMO may be recruited to a distinct MAVS signaling complex by ubiquitinated TRAF5, thereby promoting the recruitment IKKα and IKKβ, and leading to NF-κB activation. The mechanisms underlying the selective recruitment of signaling molecules to the MAVS signaling apparatus remain to be determined.
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pone-0009172-g007: Schematic representation of model for signal transduction downstream of MAVS.MAVS homodimers, induced by binding of the activated forms of the RLRs RIG-I and MDA-5, are able to signal downstream in a TRAF3 and TRAF5-dependent manner to activate IRF3/7 and in a TRAF5-dependent manner to activate NF-κB. NEMO may be recruited to the MAVS signaling complex by ubiquitinated TRAF3 and TRAF5, and may lead to IRF3 phosphorylation through the recruitment of TANK and TBK1. Alternatively, NEMO may be recruited to a distinct MAVS signaling complex by ubiquitinated TRAF5, thereby promoting the recruitment IKKα and IKKβ, and leading to NF-κB activation. The mechanisms underlying the selective recruitment of signaling molecules to the MAVS signaling apparatus remain to be determined.

Mentions: Previously, TRAF3 knockout cells were found to display a partial defect in type I interferon production in response to RNA virus infection, but an enhanced activation of NF-κB activation and production of inflammatory cytokines as a result of NIK stabilization. Our results clarify how NF-κB is activated downstream of MAVS by identifying TRAF5 as a mediator of the activation of NF-κB in addition to IRF3. The role of the TRAF family member TRAF6 has been previously implicated to be necessary for full NF-κB activation in response to viral infection and cytosolic RNA [35]. We have found that mutation of the two TRAF6 binding motifs in MAVS has little effect on its ability to activate NF-κB (Figure 1D). Also, unlike TRAF3 and TRAF5, we have been unable to detect binding of TRAF6 to the MAVS CARD (data not shown). It is possible that full activation of NF-κB may require both CARD-dependent TRAF5-dependent and CARD-independent TRAF6-dependent interactions. Also there may be differences in the use of signaling molecules between murine and human cells. Of note, murine and human TRAF6 have been shown to display significant functional differences in the induction of apoptosis and NF-κB [36]. It remains to be determined how TRAF5 but not TRAF3 selectively mediates NF-κB activation downstream of MAVS. While TRAF3 and TRAF5 may act coordinately to recruit NEMO and TANK to activate IRF3, TRAF5 alone may recruit NEMO and IKK kinase subunits to activate NF-κB (Figure 7). It remains to be investigated how such differential recruitment and/or activation may occur.


TRAF5 is a downstream target of MAVS in antiviral innate immune signaling.

Tang ED, Wang CY - PLoS ONE (2010)

Schematic representation of model for signal transduction downstream of MAVS.MAVS homodimers, induced by binding of the activated forms of the RLRs RIG-I and MDA-5, are able to signal downstream in a TRAF3 and TRAF5-dependent manner to activate IRF3/7 and in a TRAF5-dependent manner to activate NF-κB. NEMO may be recruited to the MAVS signaling complex by ubiquitinated TRAF3 and TRAF5, and may lead to IRF3 phosphorylation through the recruitment of TANK and TBK1. Alternatively, NEMO may be recruited to a distinct MAVS signaling complex by ubiquitinated TRAF5, thereby promoting the recruitment IKKα and IKKβ, and leading to NF-κB activation. The mechanisms underlying the selective recruitment of signaling molecules to the MAVS signaling apparatus remain to be determined.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2820086&req=5

pone-0009172-g007: Schematic representation of model for signal transduction downstream of MAVS.MAVS homodimers, induced by binding of the activated forms of the RLRs RIG-I and MDA-5, are able to signal downstream in a TRAF3 and TRAF5-dependent manner to activate IRF3/7 and in a TRAF5-dependent manner to activate NF-κB. NEMO may be recruited to the MAVS signaling complex by ubiquitinated TRAF3 and TRAF5, and may lead to IRF3 phosphorylation through the recruitment of TANK and TBK1. Alternatively, NEMO may be recruited to a distinct MAVS signaling complex by ubiquitinated TRAF5, thereby promoting the recruitment IKKα and IKKβ, and leading to NF-κB activation. The mechanisms underlying the selective recruitment of signaling molecules to the MAVS signaling apparatus remain to be determined.
Mentions: Previously, TRAF3 knockout cells were found to display a partial defect in type I interferon production in response to RNA virus infection, but an enhanced activation of NF-κB activation and production of inflammatory cytokines as a result of NIK stabilization. Our results clarify how NF-κB is activated downstream of MAVS by identifying TRAF5 as a mediator of the activation of NF-κB in addition to IRF3. The role of the TRAF family member TRAF6 has been previously implicated to be necessary for full NF-κB activation in response to viral infection and cytosolic RNA [35]. We have found that mutation of the two TRAF6 binding motifs in MAVS has little effect on its ability to activate NF-κB (Figure 1D). Also, unlike TRAF3 and TRAF5, we have been unable to detect binding of TRAF6 to the MAVS CARD (data not shown). It is possible that full activation of NF-κB may require both CARD-dependent TRAF5-dependent and CARD-independent TRAF6-dependent interactions. Also there may be differences in the use of signaling molecules between murine and human cells. Of note, murine and human TRAF6 have been shown to display significant functional differences in the induction of apoptosis and NF-κB [36]. It remains to be determined how TRAF5 but not TRAF3 selectively mediates NF-κB activation downstream of MAVS. While TRAF3 and TRAF5 may act coordinately to recruit NEMO and TANK to activate IRF3, TRAF5 alone may recruit NEMO and IKK kinase subunits to activate NF-κB (Figure 7). It remains to be investigated how such differential recruitment and/or activation may occur.

Bottom Line: The recognition of nucleic acids by the innate immune system during viral infection results in the production of type I interferons and the activation of antiviral immune responses.Alternatively, the activation of NF-kappaB leads to proinflammatory cytokine production.However, TRAF3-deficient cells display only a partial reduction in interferon production in response to RNA virus infection and are not defective in NF-kappaB activation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Signalling, Division of Oral Biology and Medicine, University of California Los Angeles School of Dentistry, Los Angeles, California, United States of America.

ABSTRACT
The recognition of nucleic acids by the innate immune system during viral infection results in the production of type I interferons and the activation of antiviral immune responses. The RNA helicases RIG-I and MDA-5 recognize distinct types of cytosolic RNA species and signal through the mitochondrial protein MAVS to stimulate the phosphorylation and activation of the transcription factors IRF3 and IRF7, thereby inducing type I interferon expression. Alternatively, the activation of NF-kappaB leads to proinflammatory cytokine production. The function of MAVS is dependent on both its C-terminal transmembrane (TM) domain and N-terminal caspase recruitment domain (CARD). The TM domain mediates MAVS dimerization in response to viral RNA, allowing the CARD to bind to and activate the downstream effector TRAF3. Notably, dimerization of the MAVS CARD alone is sufficient to activate IRF3, IRF7, and NF-kappaB. However, TRAF3-deficient cells display only a partial reduction in interferon production in response to RNA virus infection and are not defective in NF-kappaB activation. Here we find that the related ubiquitin ligase TRAF5 is a downstream target of MAVS that mediates both IRF3 and NF-kappaB activation. The TM domain of MAVS allows it to dimerize and thereby associate with TRAF5 and induce its ubiquitination in a CARD-dependent manner. Also, NEMO is recruited to the dimerized MAVS CARD domain in a TRAF3 and TRAF5-dependent manner. Thus, our findings reveal a possible function for TRAF5 in mediating the activation of IRF3 and NF-kappaB downstream of MAVS through the recruitment of NEMO. TRAF5 may be a key molecule in the innate response against viral infection.

Show MeSH
Related in: MedlinePlus