Virus-induced deconjugation of ISG15 dysregulates innate immunity and cellular metabolism.

Loss of SARS-CoV-2 deISGylating activity enhances innate immunity, reduces viral replication, and promotes clearance in human cells and mice.

• Why it matters: Understanding how coronaviruses subvert host immune and metabolic defenses is crucial for developing targeted antiviral strategies, as viral deISGylation may undermine innate responses.
• What they did: Researchers genetically removed the deISGylating activity of SARS-CoV-2 PLpro and used metabolomics, proteomics, and functional analyses to study its effects on immune activation and metabolism.
• The result: Findings show that viral deISGylation modulates immunity and metabolism by regulating enzymes involved in glycolysis, pentose phosphate pathway, and redox balance, revealing a key viral strategy to evade host defenses.