[Preprint] Dysregulation of innate immunity and cellular metabolism through virus-induced deISGylation, 2025, Zhu et al.

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Dysregulation of innate immunity and cellular metabolism through virus-induced deISGylation

Spoiler: Authors

Junji Zhu; GuanQun Liu; Jielin Xu; Kun Li; Christopher Goins; Huaxu Yu; Zuberwasim Sayyad; Yadi Zhou; Evangeline White; Oliver Fiehn; Shaun Stauffer; Feixiong Cheng; Michaela Gack

Interferon-stimulated gene 15 (ISG15) regulates diverse cellular responses including antiviral immunity through its conjugation to proteins, a process known as ISGylation. Several pathogens, including SARS-CoV-2, subvert ISGylation by encoding deISGylating enzymes. However, the direct targets and physiological consequences of coronaviral deISGylation remain poorly defined.

Here, we ablated the deISGylating activity of the SARS-CoV-2 papain-like protease (PLpro) and found that loss of deISGylation boosted innate immune activation, attenuated virus replication, and promoted viral clearance in human cells and in mice. Through untargeted metabolomics and ISGylome proteomics analyses, combined with functional studies, we discovered in molecular detail how the activities of key metabolic enzymes in glycolysis, the pentose phosphate pathway, and oxidative stress are controlled by PLpro deISGylation.

These findings provide fundamental new insight into how reversible ISGylation regulates immunity and metabolic processes at the molecular level and highlight viral deISGylation as a major viral tactic for rewiring immunometabolism.

Web | PDF | Preprint: BioRxiv | Open Access

 

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See also A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID (2025)

 

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Our findings highlight a broader role for ISGylation in fine-tuning central carbon metabolism in response to virus infection (or more broadly, inflammatory stress) and indicate that PLpro-mediated deISGylation promotes efficient viral replication by sustaining glycolytic output.

Our work revealed redox homeostasis as a major metabolic process dysregulated by ISGylation/deISGylation. We identified PRDX1 as a direct ISGylation target whose antioxidant activity is suppressed by ISGylation and, in turn, restored by Nsp3-mediated deISGylation. These findings show that PLpro-mediated deISGylation of PRDX1 limits oxidative stress, which intuitively seems contradictory to published reports showing that SARS-CoV-2 (as well as several other viruses) induce oxidative stress in host cells through excessive ROS production, which can contribute to viral pathogenesis by damaging host molecules. However, how viruses tolerate or actively counteract ROS induced damage to their own components (i.e., viral RNA and proteins) is poorly understood. Indeed, in addition to PRDX1, other key antioxidant enzymes —including thioredoxin (TXN), which reduces oxidized PRDX1, and the 1-Cys peroxiredoxin PRDX6— were also identified as direct deISGylation substrates of Nsp3-PLpro.