The Proteasomal Switch as a Kinetic Battleground for Influenza A Virus Pathogenesis
- 1Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Davis Heart and Lung Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
- 2Department of Physiology and Cell Biology, Davis Heart and Lung Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
- 3Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
Abstract
Influenza A virus (IAV) infection initiates a high-stakes competition for proteostatic control. While the host reconfigures its degradative machinery for defense, the virus simultaneously hijacks host proteostatic and degradative pathways to facilitate replication and evade immunity. Central to this conflict is the proteasomal switch, a process in which constitutive proteasome subunits (β1, β2, β5) are replaced by their inducible counterparts (β1i, β2i, β5i) to form the immunoproteasome (iP). Although iP is classically recognized for optimizing MHC class I antigen presentation, emerging evidence reveals more nuanced roles in IAV infections. This review synthesizes current knowledge on iP as an effector of host defense and target for viral subversion. We synthesize emerging evidence and propose working models detailing how IAV proteins may selectively interfere with proteasomal subunits to stabilize pro-viral factors. Furthermore, we examine the hypothesis that the iP functions alongside broader ubiquitin-proteasome system (UPS), endoplasmic reticulum-associated degradation (ERAD), and autophagic pathways as a proteostatic buffer to mitigate proteotoxic and oxidative stress in the infected epithelium. By evaluating how age-related proteostatic decay and viral subversion could impair cellular clearance machinery, we provide a conceptual framework for understanding how proteasomal dysregulation contributes to acute lung injury and the chronic inflammatory state termed as inflammaging. Finally, we propose a hypothesis-generating, biphasic framework for timing-dependent proteasomal modulation, contrasting preclinically supported late-stage β5i inhibition against the theoretical concept of early-stage activation to highlight translational hurdles in severe influenza.
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BibTeX
@article{soni2026proteasomal,
title = {{The Proteasomal Switch as a Kinetic Battleground for Influenza A Virus Pathogenesis}},
author = {Sourabh Soni and Vandana Anang and Pankaj Kumar and Anteneh Mehari Tizazu and Eldana G Arega and Richard S Nho and Ana L Mora and Mauricio Rojas and Jing Zhao and Yutong Zhao and Joseph S Bednash and Jeffrey C Horowitz and Jacob S Yount and Yohannes A Mebratu},
journal = {Emerging Microbes and Infections},
year = {2026},
month = oct,
doi = {10.1080/22221751.2026.2755221},
url = {https://doi.org/10.1080/22221751.2026.2755221},
note = {CC BY},
}
RIS
TY - JOUR
TI - The Proteasomal Switch as a Kinetic Battleground for Influenza A Virus Pathogenesis
AU - Sourabh Soni
AU - Vandana Anang
AU - Pankaj Kumar
AU - Anteneh Mehari Tizazu
AU - Eldana G Arega
AU - Richard S Nho
AU - Ana L Mora
AU - Mauricio Rojas
AU - Jing Zhao
AU - Yutong Zhao
AU - Joseph S Bednash
AU - Jeffrey C Horowitz
AU - Jacob S Yount
AU - Yohannes A Mebratu
PY - 2026
DA - 2026/10/26
JO - Emerging Microbes and Infections
DO - 10.1080/22221751.2026.2755221
UR - https://doi.org/10.1080/22221751.2026.2755221
AB - Influenza A virus (IAV) infection initiates a high-stakes competition for proteostatic control. While the host reconfigures its degradative machinery for defense, the virus simultaneously hijacks host proteostatic and degradative pathways to facilitate replication and evade immunity. Central to this conflict is the proteasomal switch, a process in which constitutive proteasome subunits (β1, β2, β5) are replaced by their inducible counterparts (β1i, β2i, β5i) to form the immunoproteasome (iP). Although iP is classically recognized for optimizing MHC class I antigen presentation, emerging evidence reveals more nuanced roles in IAV infections. This review synthesizes current knowledge on iP as an effector of host defense and target for viral subversion. We synthesize emerging evidence and propose working models detailing how IAV proteins may selectively interfere with proteasomal subunits to stabilize pro-viral factors. Furthermore, we examine the hypothesis that the iP functions alongside broader ubiquitin-proteasome system (UPS), endoplasmic reticulum-associated degradation (ERAD), and autophagic pathways as a proteostatic buffer to mitigate proteotoxic and oxidative stress in the infected epithelium. By evaluating how age-related proteostatic decay and viral subversion could impair cellular clearance machinery, we provide a conceptual framework for understanding how proteasomal dysregulation contributes to acute lung injury and the chronic inflammatory state termed as inflammaging. Finally, we propose a hypothesis-generating, biphasic framework for timing-dependent proteasomal modulation, contrasting preclinically supported late-stage β5i inhibition against the theoretical concept of early-stage activation to highlight translational hurdles in severe influenza.
SN - 2222-1751
ER -