Type I interferon/STAT1 signaling regulates UBE2M-mediated antiviral innate immunity in a negative feedback manner

  • Cell Rep. 2023 Jan 31;42(1):112002. doi: 10.1016/j.celrep.2023.112002.
Xianghui Kong  1 ,  Xinliang Lu  2 ,  Shibo Wang  3 ,  Jiayue Hao  3 ,  Danfeng Guo  4 ,  Hao Wu  5 ,  Yu Jiang  6 ,  Yi Sun  7 ,  Jianli Wang  8 ,  Gensheng Zhang  9 ,  Zhijian Cai  10
Affiliations
  • 1. Institute of Immunology, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou 310006, China.
  • 2. Institute of Immunology, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou 310006, China. Electronic address: [email protected].
  • 3. Institute of Immunology, and Department of Orthopedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
  • 4. Henan Key Laboratory for Digestive Organ Transplantation, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
  • 5. Gastroenterology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.
  • 6. Department of Clinical Laboratory Medicine, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
  • 7. Cancer Institute of the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.
  • 8. Institute of Immunology, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou 310006, China. Electronic address: [email protected].
  • 9. Department of Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. Electronic address: [email protected].
  • 10. Institute of Immunology, and Department of Orthopedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. Electronic address: [email protected].
PMID: 36662617 DOI: 10.1016/j.celrep.2023.112002
Abstract

Type I interferon (IFN-I) signaling is central to inducing Antiviral innate immunity. However, the mechanisms for IFN-I signaling self-regulation are still largely unknown. Here, we report that RNA virus-infected macrophages with UBE2M deficiency produced decreased IFN-I expression in a RIG-I-dependent manner, causing an aggravated viral Infection. Mechanistically, UBE2M inhibits RIG-I degradation by preventing the interaction of RIG-I and E3 Ligase STUB1, resulting in Antiviral IFN-I signaling activation. Simultaneously, IFN-I signaling-activated STAT1 facilitates the transcription of TRIM21, leading to increased UBE2M degradation and blunted Antiviral immunity. Translationally, oral administration of milk-derived extracellular vesicles containing RING domain-truncated TRIM21 (TRIM21-ΔRING) lacking E3 Ligase activity efficiently transfers TRIM21-ΔRING into macrophages. TRIM21-ΔRING suppresses UBE2M degradation by competitively binding to UBE2M with TRIM21, thereby enhancing Antiviral immunity. Overall, we reveal a negative feedback loop of IFN-I signaling and develop a reagent to improve innate immunity against RNA viruses.

Keywords
CP: Immunology; IFN-I; Macrophage; RIG-I; RNA virus; UBE2M; negative feedback.
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