Liver Survival Protein USP18 Protects Cells From Proteotoxic Stress

The liver faces a constant burden of proteotoxic stress, the damage that accumulates when misfolded proteins pile up faster than cells can clear them. Because hepatocytes carry exceptionally high protein turnover, they are especially vulnerable when the proteasome—the cell’s protein-disposal machinery—fails. A new study published in Cell Communication and Signaling identifies a non-canonical protective pathway built on the interferon-stimulated gene USP18 and its partner STAT2, which appears to keep liver cells alive under this kind of proteostatic collapse.

The researchers, led by Abhishek Sen, Saheli Chowdhury and Partha Chakrabarti, induced proteotoxic stress in C57BL/6 mice and in HepG2 liver cells using the proteasome inhibitors bortezomib and MG132. They then combined transcriptomic analysis, quantitative PCR, immunoblotting, immunofluorescence, biochemical fractionation, immunoprecipitation, site-directed mutagenesis, adenoviral gene delivery and apoptosis assays to trace how type I interferon signalling behaves when protein quality control breaks down.

The results showed that proteasomal inhibition suppresses basal type I interferon signalling in two ways at once. It impairs the nuclear localization of IRF9, a component of the interferon-stimulated gene factor complex, and it downregulates a subset of interferon-stimulated genes. At the same time, the proteins encoded by these genes physically redistribute into detergent-insoluble aggregates, meaning the interferon response is silenced both transcriptionally and through protein insolubility.

Among the interferon-stimulated genes examined, USP18 stood out as the principal determinant protecting hepatocytes from proteotoxic apoptosis. Notably, this cytoprotective effect did not depend on USP18’s catalytic activity. Instead, it required the protein’s scaffolding function, mediated by isoleucine-60 and its interaction with STAT2. The authors report that USP18 formed reversible cytoplasmic condensates that were distinct from p62-positive aggresomes, suggesting a controlled, liquid-like sequestration rather than irreversible aggregation.

Priming cells with interferon-alpha changed the outcome markedly. IFNα treatment preserved USP18 in its soluble form, restored interferon-stimulated gene expression and substantially reduced proteotoxic injury both in cultured hepatocytes and in vivo. Conversely, genetic depletion of USP18 or disruption of its interaction with STAT2 abolished the protection conferred by IFNα priming, pinpointing the USP18–STAT2 axis as the required effector of this survival response.

The study’s conclusions frame proteotoxic liver injury as a failure of hepatic resilience driven by coordinated repression of basal interferon signalling. Because the protective function operates independently of USP18’s enzymatic activity, the work points to scaffolding interactions and interferon pathway modulation as potential therapeutic targets for conditions in which misfolded proteins overwhelm liver cells. As with any preclinical cell and mouse model study, however, these findings describe mechanisms in experimental systems and will require further investigation before any clinical application.

Subject of Research: How the USP18–STAT2 interferon signalling axis protects liver cells from proteotoxic stress

Article Title: USP18-STAT2 axis enhances hepatic resilience under proteotoxic stress

Article References: Sen, A., Chowdhury, S., & Chakrabarti, P. (2026). USP18-STAT2 axis enhances hepatic resilience under proteotoxic stress. Cell Communication and Signaling. https://doi.org/10.1186/s12964-026-03330-z

Image Credits: AI Generated

DOI: 10.1186/s12964-026-03330-z

Keywords: USP18, STAT2, proteotoxic stress, liver, type I interferon, proteasome, proteostasis, hepatocytes, apoptosis, IRF9, interferon-stimulated genes, cytoprotection