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An Internally Translated MAVS Variant Exposes Its Amino-terminal TRAF-Binding Motifs to Deregulate Interferon Induction.

Minassian A, Zhang J, He S, Zhao J, Zandi E, Saito T, Liang C, Feng P - PLoS Pathog. (2015)

Bottom Line: By contrast, MAVS50 inhibits the IRF activation and suppresses IFN induction.Ablation of the TRAF-binding motif of MAVS50 impaired its inhibitory effect on IRF activation and IFN induction.These results collectively identify a new means by which signaling events is differentially regulated via exposing key internally embedded interaction motifs, implying a more ubiquitous regulatory role of truncated proteins arose from internal translation and other related mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.

ABSTRACT
Activation of pattern recognition receptors and proper regulation of downstream signaling are crucial for host innate immune response. Upon infection, the NF-κB and interferon regulatory factors (IRF) are often simultaneously activated to defeat invading pathogens. Mechanisms concerning differential activation of NF-κB and IRF are not well understood. Here we report that a MAVS variant inhibits interferon (IFN) induction, while enabling NF-κB activation. Employing herpesviral proteins that selectively activate NF-κB signaling, we discovered that a MAVS variant of ~50 kDa, thus designated MAVS50, was produced from internal translation initiation. MAVS50 preferentially interacts with TRAF2 and TRAF6, and activates NF-κB. By contrast, MAVS50 inhibits the IRF activation and suppresses IFN induction. Biochemical analysis showed that MAVS50, exposing a degenerate TRAF-binding motif within its N-terminus, effectively competed with full-length MAVS for recruiting TRAF2 and TRAF6. Ablation of the TRAF-binding motif of MAVS50 impaired its inhibitory effect on IRF activation and IFN induction. These results collectively identify a new means by which signaling events is differentially regulated via exposing key internally embedded interaction motifs, implying a more ubiquitous regulatory role of truncated proteins arose from internal translation and other related mechanisms.

No MeSH data available.


Related in: MedlinePlus

A hypothetical model on MAVS50 in modulating MAVS70-dependent signaling.Upon receiving upstream activation signal, MAVS70 forms large oligomer that triggers both NF-κB activation and IRF activation and IFN induction. MAVS50 interacts with MAVS70 and integrates into the MAVS70 oligomers. MAVS50 recruits significant portion of TRAF6 and TRAF2 with its N-terminally exposed TRAF-binding motifs, resulting in the inhibition of MAVS70-dependent NF-κB and IRF activation. The oligomer containing MAVS70 and MAVS50 activates only NF-κB, but not IRF-IFN branch. As such, MAVS50 selectively inhibits IFN induction. See discussion section for more detail.
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ppat.1005060.g007: A hypothetical model on MAVS50 in modulating MAVS70-dependent signaling.Upon receiving upstream activation signal, MAVS70 forms large oligomer that triggers both NF-κB activation and IRF activation and IFN induction. MAVS50 interacts with MAVS70 and integrates into the MAVS70 oligomers. MAVS50 recruits significant portion of TRAF6 and TRAF2 with its N-terminally exposed TRAF-binding motifs, resulting in the inhibition of MAVS70-dependent NF-κB and IRF activation. The oligomer containing MAVS70 and MAVS50 activates only NF-κB, but not IRF-IFN branch. As such, MAVS50 selectively inhibits IFN induction. See discussion section for more detail.

Mentions: How does MAVS50 differentially alter MAVS70-dependent signaling, i.e., inhibiting IRF activation and IFN induction while weakly stimulating NF-κB activation? Based on our findings, we propose the following hypothetical model that summarizes the action of MAVS50 in specific inhibiting IFN induction (Fig 7). Upon stimulation such as activated RIG-I, MAVS70 forms large oligomers in the form of prion-like polymers or fibrils, resulting potent activation of both NF-κB and IRF transcription factors. By positioning TRAF-binding motifs at the very N-terminus, MAVS50 interacts more strongly with TRAF6, and likely TRAF2, than MAVS70. In doing so, MAVS50 efficiently sequesters TRAF6 from the prion-like MAVS70 polymers, attenuating the MAVS70-mediated signaling. When activated MAVS70 undergoes oligomerization, MAVS50 is induced to oligomerize via interacting with MAVS70. Given its high affinity for TRAF adaptor molecules, oligomerized MAVS50 is sufficient to induce NF-κB activation, but not IRF activation and IFN induction. Sum of both results is the specific inhibition of IFN induction and modest NF-κB activation by MAVS50. Then, how does MAVS70 activate both NF-κB and IRF, while MAVS50 activates only NF-κB. In SeV-infected or vGAT-expressing cells, MAVS70 migrated into the Triton X-100-insoluble fraction, whereas MAVS50 remained in the soluble fraction. In transfected 293T cells, MAVS50 forms smaller oligomers than MAVS70. These findings largely agree with the notion that higher order of MAVS70 oligomers form fibrils and precipitates out from Triton X-100-containing solution, whereas MAVS50 does not [8,31]. Together with TBK-1 that phosphorylates an IRF3-binding domain, MAVS70 fibrils provide a signaling platform that enables IRF3 activation and IFN induction [37]. Thus, it is conceivable that MAVS70 and MAVS50 form at least two types of oligomers that are of distinct sizes. The large oligomeric MAVS70 is capable of activating NF-κB and IRF, while the smaller MAVS50-containing oligomer only activates NF-κB. Perhaps, integration of MAVS50 into the MAVS70 larger oligomers shifts the signaling capacity of the complex from activating both NF-κB and IRF to that activating only NF-κB. This possibility remains to be formally tested in the future.


An Internally Translated MAVS Variant Exposes Its Amino-terminal TRAF-Binding Motifs to Deregulate Interferon Induction.

Minassian A, Zhang J, He S, Zhao J, Zandi E, Saito T, Liang C, Feng P - PLoS Pathog. (2015)

A hypothetical model on MAVS50 in modulating MAVS70-dependent signaling.Upon receiving upstream activation signal, MAVS70 forms large oligomer that triggers both NF-κB activation and IRF activation and IFN induction. MAVS50 interacts with MAVS70 and integrates into the MAVS70 oligomers. MAVS50 recruits significant portion of TRAF6 and TRAF2 with its N-terminally exposed TRAF-binding motifs, resulting in the inhibition of MAVS70-dependent NF-κB and IRF activation. The oligomer containing MAVS70 and MAVS50 activates only NF-κB, but not IRF-IFN branch. As such, MAVS50 selectively inhibits IFN induction. See discussion section for more detail.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4519330&req=5

ppat.1005060.g007: A hypothetical model on MAVS50 in modulating MAVS70-dependent signaling.Upon receiving upstream activation signal, MAVS70 forms large oligomer that triggers both NF-κB activation and IRF activation and IFN induction. MAVS50 interacts with MAVS70 and integrates into the MAVS70 oligomers. MAVS50 recruits significant portion of TRAF6 and TRAF2 with its N-terminally exposed TRAF-binding motifs, resulting in the inhibition of MAVS70-dependent NF-κB and IRF activation. The oligomer containing MAVS70 and MAVS50 activates only NF-κB, but not IRF-IFN branch. As such, MAVS50 selectively inhibits IFN induction. See discussion section for more detail.
Mentions: How does MAVS50 differentially alter MAVS70-dependent signaling, i.e., inhibiting IRF activation and IFN induction while weakly stimulating NF-κB activation? Based on our findings, we propose the following hypothetical model that summarizes the action of MAVS50 in specific inhibiting IFN induction (Fig 7). Upon stimulation such as activated RIG-I, MAVS70 forms large oligomers in the form of prion-like polymers or fibrils, resulting potent activation of both NF-κB and IRF transcription factors. By positioning TRAF-binding motifs at the very N-terminus, MAVS50 interacts more strongly with TRAF6, and likely TRAF2, than MAVS70. In doing so, MAVS50 efficiently sequesters TRAF6 from the prion-like MAVS70 polymers, attenuating the MAVS70-mediated signaling. When activated MAVS70 undergoes oligomerization, MAVS50 is induced to oligomerize via interacting with MAVS70. Given its high affinity for TRAF adaptor molecules, oligomerized MAVS50 is sufficient to induce NF-κB activation, but not IRF activation and IFN induction. Sum of both results is the specific inhibition of IFN induction and modest NF-κB activation by MAVS50. Then, how does MAVS70 activate both NF-κB and IRF, while MAVS50 activates only NF-κB. In SeV-infected or vGAT-expressing cells, MAVS70 migrated into the Triton X-100-insoluble fraction, whereas MAVS50 remained in the soluble fraction. In transfected 293T cells, MAVS50 forms smaller oligomers than MAVS70. These findings largely agree with the notion that higher order of MAVS70 oligomers form fibrils and precipitates out from Triton X-100-containing solution, whereas MAVS50 does not [8,31]. Together with TBK-1 that phosphorylates an IRF3-binding domain, MAVS70 fibrils provide a signaling platform that enables IRF3 activation and IFN induction [37]. Thus, it is conceivable that MAVS70 and MAVS50 form at least two types of oligomers that are of distinct sizes. The large oligomeric MAVS70 is capable of activating NF-κB and IRF, while the smaller MAVS50-containing oligomer only activates NF-κB. Perhaps, integration of MAVS50 into the MAVS70 larger oligomers shifts the signaling capacity of the complex from activating both NF-κB and IRF to that activating only NF-κB. This possibility remains to be formally tested in the future.

Bottom Line: By contrast, MAVS50 inhibits the IRF activation and suppresses IFN induction.Ablation of the TRAF-binding motif of MAVS50 impaired its inhibitory effect on IRF activation and IFN induction.These results collectively identify a new means by which signaling events is differentially regulated via exposing key internally embedded interaction motifs, implying a more ubiquitous regulatory role of truncated proteins arose from internal translation and other related mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.

ABSTRACT
Activation of pattern recognition receptors and proper regulation of downstream signaling are crucial for host innate immune response. Upon infection, the NF-κB and interferon regulatory factors (IRF) are often simultaneously activated to defeat invading pathogens. Mechanisms concerning differential activation of NF-κB and IRF are not well understood. Here we report that a MAVS variant inhibits interferon (IFN) induction, while enabling NF-κB activation. Employing herpesviral proteins that selectively activate NF-κB signaling, we discovered that a MAVS variant of ~50 kDa, thus designated MAVS50, was produced from internal translation initiation. MAVS50 preferentially interacts with TRAF2 and TRAF6, and activates NF-κB. By contrast, MAVS50 inhibits the IRF activation and suppresses IFN induction. Biochemical analysis showed that MAVS50, exposing a degenerate TRAF-binding motif within its N-terminus, effectively competed with full-length MAVS for recruiting TRAF2 and TRAF6. Ablation of the TRAF-binding motif of MAVS50 impaired its inhibitory effect on IRF activation and IFN induction. These results collectively identify a new means by which signaling events is differentially regulated via exposing key internally embedded interaction motifs, implying a more ubiquitous regulatory role of truncated proteins arose from internal translation and other related mechanisms.

No MeSH data available.


Related in: MedlinePlus