Why the study?
The arterivirus nsp4-encoded 3C-like protease is an attractive target for antivirals, but understanding how it cleaves NEMO to antagonize type I IFN production remained incomplete.
The study reveals that arterivirus nsp4 cleaves NEMO at multiple sites to suppress type I interferon production, expanding knowledge of viral immune evasion mechanisms.
May inform arterivirus antiviral strategies; extends IFN evasion models beyond single-site cleavage.
The arterivirus nsp4-encoded 3C-like protease (3CL pro ) plays an important role in virus replication and immune evasion, making it an attractive target for antiviral therapeutics. Previous work suggested that PRRSV nsp4 suppresses type I IFN production by cleaving NEMO at a single site. In contrast, the present study demonstrates that both EAV and PRRSV nsp4 cleave NEMO at multiple sites and that this strategy is essential for disruption of type I IFN production. Moreover, we reveal that EAV nsp4 also cleaves NEMO at glutamine 205 (Q205), which is not targeted by PRRSV nsp4. Notably, targeting a glutamine in NEMO for cleavage has been observed only with picornavirus 3C proteases (3C pro ) and coronavirus 3CL pro . In aggregate, our work expands knowledge of the innate immune evasion mechanisms associated with NEMO cleavage by arterivirus nsp4 and describes a novel substrate recognition characteristic of EAV nsp4.
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Chen et al. (2019) studied this question.
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