Viral deISGylation holds the key to the metabolic kingdom.

Viral deISGylation broadly relieves ISG15-mediated restriction of key metabolic pathways to promote viral replication.

• Why it matters: Understanding how viruses counteract host immune modifications is crucial for developing antiviral strategies, as the full physiological impact of ISG15 modification remains unclear.
• What they did: Zhu et al. examined the effects of ISG15 modification and its reversal by virus-encoded deISGylases on cellular metabolism, highlighting the broad restriction imposed by ISG15.
• The result: The study suggests that deISGylation enables viral replication by relieving ISG15-driven metabolic restrictions, revealing a key host-pathogen interaction in immune evasion.