Functional Comparison of Molluscum Contagiosum Virus vFLIP MC159 with Murine Cytomegalovirus M36/vICA and M45/vIRA Proteins

Hüttmann, Julia; Krause, Eva; Schommartz, Tim; Brune, Wolfram

doi:10.1128/jvi.02729-15

Cited by 16 publications

(21 citation statements)

References 54 publications

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“…NEMO was not immunoprecipitated under these conditions, showing the specificity of the immunoprecipitation conditions. MC159 was also coimmunoprecipitated with FLAG-NEMO, in agreement with data from previous reports (14,35). Thus, these results suggest that MC159 antagonized NEMO polyubiquitination, likely by interacting with NEMO, and warranted further study into how MC159 prevented NEMO polyubiquitination.…”

supporting

confidence: 90%

“…MC159 does not inhibit RIP1-NEMO interactions. Our and data and those reported previously by others showed that MC159 coimmunoprecipitates with RIP1 (39,40) and NEMO (14,35). IKK must interact with RIP1 for NF-B activation (23).…”

supporting

confidence: 89%

“…Thus, a strategic allowance of RIP1, polyubiquitination would decrease signaling events associated with cell death and increase events associated with virus survival. There are reports that show that MC159 inhibits TNFinduced necroptosis (35) and programmed necrosis (39,63), which support this hypothesis. MC159 is already known to bind to and inhibit procaspase-8 to inhibit apoptosis (8,9,43).…”

Section: Discussionmentioning

confidence: 67%

“…However, there are several reports showing that MC159 activates the NF-B pathway when MC159 is expressed at low levels (14,35,68,69). This begs the question of which phenotype has biological relevance.…”

Section: Discussionmentioning

confidence: 98%

“…This report focuses on MC159 inhibition of NF-B activation (14,35,40,68). However, there are several reports showing that MC159 activates the NF-B pathway when MC159 is expressed at low levels (14,35,68,69).…”

Section: Discussionmentioning

confidence: 99%

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Molluscum Contagiosum Virus MC159 Abrogates cIAP1-NEMO Interactions and Inhibits NEMO Polyubiquitination

Biswas

Shisler

2017

J Virol

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Molluscum contagiosum virus (MCV) is a dermatotropic poxvirus that causes benign skin lesions. MCV lesions persist because of virally encoded immune evasion molecules that inhibit antiviral responses. The MCV MC159 protein suppresses NF-B activation, a powerful antiviral response, via interactions with the NF-B essential modulator (NEMO) subunit of the IB kinase (IKK) complex. Binding of MC159 to NEMO does not disrupt the IKK complex, implying that MC159 prevents IKK activation via an as-yet-unidentified strategy. Here, we demonstrated that MC159 inhibited NEMO polyubiquitination, a posttranslational modification required for IKK and downstream NF-B activation. Because MCV cannot be propagated in cell culture, MC159 was expressed independent of infection or during a surrogate vaccinia virus infection to identify how MC159 prevented polyubiquitination. Cellular inhibitor of apoptosis protein 1 (cIAP1) is a cellular E3 ligase that ubiquitinates NEMO. Mutational analyses revealed that MC159 and cIAP1 each bind to the same NEMO region, suggesting that MC159 may competitively inhibit cIAP1-NEMO interactions. Indeed, MC159 prevented cIAP1-NEMO interactions. MC159 also diminished cIAP1-mediated NEMO polyubiquitination and cIAP1-induced NF-B activation. These data suggest that MC159 competitively binds to NEMO to prevent cIAP1-induced NEMO polyubiquitination. To our knowledge, this is the first report of a viral protein disrupting NEMO-cIAP1 interactions to strategically suppress IKK activation. All viruses must antagonize antiviral signaling events for survival. We hypothesize that MC159 inhibits NEMO polyubiquitination as a clever strategy to manipulate the host cell environment to the benefit of the virus. IMPORTANCE Molluscum contagiosum virus (MCV) is a human-specific poxvirus that causes persistent skin neoplasms. The persistence of MCV has been attributed to viral downregulation of host cell immune responses such as NF-B activation. We show here that the MCV MC159 protein interacts with the NEMO subunit of the IKK complex to prevent NEMO interactions with the cIAP1 E3 ubiquitin ligase. This interaction correlates with a dampening of cIAP1 to polyubiquitinate NEMO and to activate NF-B. This inhibition of cIAP1-NEMO interactions is a new viral strategy to minimize IKK activation and to control NEMO polyubiquitination. This research provides new insights into mechanisms that persistent viruses may use to cause long-term infection of host cells.

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supporting

confidence: 90%

supporting

confidence: 89%