HERC5-mediated co-translational ISGylation in innate immunity: molecular mechanisms, context-dependent regulation, and therapeutic potential
Abstract
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.
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BibTeX
@article{huang2026herc5mediated,
title = {{HERC5-mediated co-translational ISGylation in innate immunity: molecular mechanisms, context-dependent regulation, and therapeutic potential}},
author = {Xiaomei Huang and Fengdie Huang and Dongrong Luo and Shiying Li and Qinglan Lu and Jinjiu Huang and Lina Yang and Ruolin Li},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1979218},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1979218},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - HERC5-mediated co-translational ISGylation in innate immunity: molecular mechanisms, context-dependent regulation, and therapeutic potential
AU - Xiaomei Huang
AU - Fengdie Huang
AU - Dongrong Luo
AU - Shiying Li
AU - Qinglan Lu
AU - Jinjiu Huang
AU - Lina Yang
AU - Ruolin Li
PY - 2026
DA - 2026/11/02
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1979218
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1979218
AB - 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.
SN - 1664-3224
ER -