HERC5-mediated co-translational ISGylation in innate immunity: molecular mechanisms, context-dependent regulation, and therapeutic potential

HERC5 is the predominant E3 ligase for interferon-stimulated gene 15 (ISG15) in human cells and is now considered a central component of interferon-driven innate immune regulation. Unlike conventional E3 ligases that primarily modify mature proteins, HERC5 has been reported to mediate co-translational ISGylation by associating with ribosomes and modifying nascent polypeptides during protein synthesis, providing a mechanistic link between interferon activation, protein modification, and rapid cellular adaptation during immune responses. Accumulating evidence suggests that HERC5-mediated ISGylation contributes to multiple aspects of antiviral defense, amplification of interferon signaling, pathogen–host interactions, and immune homeostasis. Beyond its canonical antiviral functions, emerging studies reveal that dysregulated HERC5 activity contributes to immune-associated pathological processes, including inflammatory disorders, tumor-associated immune regulation, and stress-induced cellular adaptation. However, the molecular principles that determine how HERC5 generates distinct biological outcomes across cellular and pathological contexts remain incompletely understood. In this Review, we critically synthesize selected mechanistic, experimental, and clinical evidence on HERC5-mediated co-translational ISGylation and propose a context-dependent regulatory framework in which HERC5 functions as an interferon-responsive ISGylation hub. We discuss three interconnected regulatory axes: the interferon–ISGylation axis, which governs antiviral immunity and innate immune signaling amplification; the stress adaptation and homeostasis axis, which links HERC5 activity to cellular adaptation and proteome regulation during immune responses; and the disease-associated rewiring axis, which describes how altered HERC5-mediated ISGylation contributes to pathological immune signaling. These axes provide a conceptual framework for comparing experimentally established mechanisms with disease-associated observations rather than implying a universal causal pathway. Furthermore, we highlight the emerging translational potential of HERC5 as a biomarker and therapeutic target, including nanobody-based ISGylation-targeting chimeras (NITACs) as a programmable strategy for modulating ISGylation-dependent immune pathways. Collectively, this Review highlights HERC5-mediated co-translational ISGylation as an emerging regulatory interface linking innate immunity, proteostasis, and immune-associated diseases.