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December 16, 2019: New findings on the immune-evasion mechanisms of Herpesviruses

Monday, 16. December 2019

Herpesviruses have developed numerous ways to evade the immune defense of the host cells (the so-called immune-evasion). Using the murine cytomegalovirus (MCMV) as a model, a new principle of viral immune evasion was discovered.

A recently published Nature Microbiology publication reveals that herpesviruses can specifically induce the aggregation of important signal molecules and their degradation by selective autophagy in order to block innate antiviral responses such as the activation of NF-κB and the induction of necroptosis. The data suggest that induced protein aggregation in combination with selective autophagy of aggregates represents a conserved viral immune-evasion mechanism.

Elena Muscolino, first author and PhD student in the HPI Research Department “Virus-Host-Interaction” explains what the publication is all about:

 

What exactly did you investigate?

We investigated how viruses can exploit autophagy, a cellular self-eating process, to inhibit innate antiviral immune defenses of the host cell. Specifically we focused on the molecular mechanism used by the mouse cytomegalovirus (MCMV) M45 protein to degrade two important cellular signaling molecules, NEMO and RIPK1. These two proteins are involved in inflammatory signaling and programmed cell death. We wanted to unravel how a viral protein can redirect these molecules to autophagosomes in order to induce their degradation. We also investigated whether this mechanism is unique to MCMV or shared by other viruses of the herpesvirus family.

 

What new insights have been obtained?

We could show that M45 induces the degradation of NEMO and RIPK1 by a two-step process. First, M45 binds to the cellular proteins and induces their aggregation. Then, M45 recruits two cellular adaptor molecules to direct the aggregates to autophagosomes. Thereby, the virus prevents activation of the pro-inflammatory transcription factor NF-κB and the induction of programmed necrosis. We discovered a specific sequence motif within M45, which we called IPAM (induced protein aggregation motif). This motif is required for aggregation, inhibition of necroptosis, and viral pathogenesis in mice. Remarkably, we found that the IPAM is conserved in more than 70 large DNA viruses (herpesviruses, baculoviruses, and giant viruses), suggesting that induced protein aggregation might be a widely-used mechanism. As an example for this conservation we showed that the mechanism of induced aggregation and degradation is also used by the herpes simplex virus ICP6 protein.

Publication:

Muscolino E, Schmitz R, Loroch S, Caragliano E, Schneider C, Rizzato M, Kim YH, Krause E, Lisnic VJ, Sickmann A, Reimer R, Ostermann E, Brune W. Herpesviruses induce aggregation and selective autophagy of host signalling proteins NEMO and RIPK1 as an immune-evasion mechanism. Nature Microbiology 2019. DOI: 10.1038/s41564-019-0624-1