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<p>Although significant progressions in antiviral studies of IFNβ have been demonstrated, the role of the proteasome in modulating cross-talk between TBK1-IFNβ signaling and viral replication during viral infection is not fully elucidated. Here, we discover that deficiency of REGγ, a proteasome activator, significantly reduces IFNβ production and increases viral replications in mice, leading to increased mortality in virus infection models. Our mechanistic study indicates that REGγ interacts with and degrades the protein phosphatase subunit Protein Phosphatase 2 Catalytic Subunit Beta (PPP2CB). This degradation disrupts the dephosphorylation of TBK1 and its interaction with IRF3, resulting in the activation of IFNβ-mediated antiviral signaling. In response to viral infection, up-regulation of REGγ in macrophages accelerates the degradation of PPP2CB, which increases the activation of TBK1-IRF3-IFNβ axis and thereby restricts viral replications and pathology. Interestingly, IFNβ enhances REGγ expression in viral infection, forming a positive feedback regulatory loop. In conclusion, our work demonstrates that REGγ is a positive modulator of IFNβ signaling during antiviral response, highlighting that this procedure is regulated via REGγ degradation of PPP2CB and provides a new insight into the coordination between antiviral response and proteasome activity. Thus, REGγ-proteasome activity and phosphatase PPP2CB may be potential targets in host defense against viruses.</p>

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REGγ regulates antiviral response by activating TBK1-IFNβ signaling through degradation of PPP2CB

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月30日

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  • Yi Li,
  • Pei Wang,
  • Jiamin Ma,
  • Qing Tu,
  • Yuan Yuan,
  • Ying Chen,
  • Lin Wang,
  • Yuwei Chen,
  • Feng Chen,
  • Suvi Biesinger,
  • Henry J. Li,
  • Jinbao Li,
  • Liangfang Yao

摘要

Although significant progressions in antiviral studies of IFNβ have been demonstrated, the role of the proteasome in modulating cross-talk between TBK1-IFNβ signaling and viral replication during viral infection is not fully elucidated. Here, we discover that deficiency of REGγ, a proteasome activator, significantly reduces IFNβ production and increases viral replications in mice, leading to increased mortality in virus infection models. Our mechanistic study indicates that REGγ interacts with and degrades the protein phosphatase subunit Protein Phosphatase 2 Catalytic Subunit Beta (PPP2CB). This degradation disrupts the dephosphorylation of TBK1 and its interaction with IRF3, resulting in the activation of IFNβ-mediated antiviral signaling. In response to viral infection, up-regulation of REGγ in macrophages accelerates the degradation of PPP2CB, which increases the activation of TBK1-IRF3-IFNβ axis and thereby restricts viral replications and pathology. Interestingly, IFNβ enhances REGγ expression in viral infection, forming a positive feedback regulatory loop. In conclusion, our work demonstrates that REGγ is a positive modulator of IFNβ signaling during antiviral response, highlighting that this procedure is regulated via REGγ degradation of PPP2CB and provides a new insight into the coordination between antiviral response and proteasome activity. Thus, REGγ-proteasome activity and phosphatase PPP2CB may be potential targets in host defense against viruses.