Coronavirus Exploitation of Ubiquitination and Selective Autophagy to Control Innate Immunity: Mechanisms, Systems Logic, and Therapeutic Opportunities.
- 1Institute of Animal Science, Ningxia Academy of Agricultural and Forestry Sciences, Yinchuan 750002, China.
- 2School of Animal Science and Technology, Ningxia University, Yinchuan 750021, China.
Abstract
Coronaviruses replicate in membrane-rich cytoplasmic niches while confronting innate immune systems whose activation, signal propagation, and termination are extensively controlled by ubiquitin and autophagy. These two regulatory systems are often discussed separately. Yet they form a coupled information-and-disposal network: ubiquitin chains encode the identity and fate of immune proteins or viral cargo, whereas selective autophagy receptors read these signals and route substrates to lysosomes. Coronaviruses exploit this coupling at several levels. Papain-like proteases remove ubiquitin and ISG15 from antiviral factors; structural, nonstructural, and accessory proteins redirect host ubiquitin ligases or destabilize immune adaptors; and viral proteins remodel autophagosome biogenesis, mitophagy, lysosome function, and selective virophagy. These activities do more than globally suppress immunity. They delay early interferon production, reshape inflammatory signaling, preserve replication organelles, adjust mitochondrial quality control, and protect viral proteins from cargo-selective degradation. Importantly, the outcome is context dependent. Autophagy initiation can support membrane supply or suppress mitochondrial antiviral signaling, whereas completion of autophagic flux can eliminate viral material and restrain damaging inflammation. Likewise, K48-linked ubiquitination may remove antiviral proteins, but nondegradative K63- or M1-linked chains can either assemble antiviral signalosomes or promote pathological NF-κB activity. Here, we synthesize evidence from human and animal coronaviruses to propose that viral immune evasion is governed by spatially and temporally selective rewiring rather than indiscriminate inhibition. We distinguish mechanisms demonstrated during infection from those inferred from ectopic expression, identify points of convergence among RIG-I-like receptor, cGAS-STING, NF-κB, inflammasome, and autophagy pathways, and discuss why apparently contradictory observations often reflect differences in flux, cell type, infection stage, and viral lineage. This integrated view highlights viral proteases, host E3 ligase-substrate interfaces, autophagy receptors, and organelle contact sites as therapeutic nodes, while emphasizing that interventions must preserve the homeostatic functions of ubiquitin and autophagy.
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BibTeX
@article{wang2026coronavirus,
title = {{Coronavirus Exploitation of Ubiquitination and Selective Autophagy to Control Innate Immunity: Mechanisms, Systems Logic, and Therapeutic Opportunities.}},
author = {Pan Wang and Yuxi Zhao and Yuqiu Yang and Juan Zhang and Junfang Wu and Jiandong Wang},
journal = {Viruses},
year = {2026},
month = sep,
doi = {10.3390/v18101068},
url = {https://europepmc.org/article/MED/42943988},
note = {CC BY},
}
RIS
TY - JOUR
TI - Coronavirus Exploitation of Ubiquitination and Selective Autophagy to Control Innate Immunity: Mechanisms, Systems Logic, and Therapeutic Opportunities.
AU - Pan Wang
AU - Yuxi Zhao
AU - Yuqiu Yang
AU - Juan Zhang
AU - Junfang Wu
AU - Jiandong Wang
PY - 2026
DA - 2026/09/26
JO - Viruses
DO - 10.3390/v18101068
UR - https://europepmc.org/article/MED/42943988
AB - Coronaviruses replicate in membrane-rich cytoplasmic niches while confronting innate immune systems whose activation, signal propagation, and termination are extensively controlled by ubiquitin and autophagy. These two regulatory systems are often discussed separately. Yet they form a coupled information-and-disposal network: ubiquitin chains encode the identity and fate of immune proteins or viral cargo, whereas selective autophagy receptors read these signals and route substrates to lysosomes. Coronaviruses exploit this coupling at several levels. Papain-like proteases remove ubiquitin and ISG15 from antiviral factors; structural, nonstructural, and accessory proteins redirect host ubiquitin ligases or destabilize immune adaptors; and viral proteins remodel autophagosome biogenesis, mitophagy, lysosome function, and selective virophagy. These activities do more than globally suppress immunity. They delay early interferon production, reshape inflammatory signaling, preserve replication organelles, adjust mitochondrial quality control, and protect viral proteins from cargo-selective degradation. Importantly, the outcome is context dependent. Autophagy initiation can support membrane supply or suppress mitochondrial antiviral signaling, whereas completion of autophagic flux can eliminate viral material and restrain damaging inflammation. Likewise, K48-linked ubiquitination may remove antiviral proteins, but nondegradative K63- or M1-linked chains can either assemble antiviral signalosomes or promote pathological NF-κB activity. Here, we synthesize evidence from human and animal coronaviruses to propose that viral immune evasion is governed by spatially and temporally selective rewiring rather than indiscriminate inhibition. We distinguish mechanisms demonstrated during infection from those inferred from ectopic expression, identify points of convergence among RIG-I-like receptor, cGAS-STING, NF-κB, inflammasome, and autophagy pathways, and discuss why apparently contradictory observations often reflect differences in flux, cell type, infection stage, and viral lineage. This integrated view highlights viral proteases, host E3 ligase-substrate interfaces, autophagy receptors, and organelle contact sites as therapeutic nodes, while emphasizing that interventions must preserve the homeostatic functions of ubiquitin and autophagy.
SN - 1999-4915
ER -