1. Academic Validation
  2. FBXO6 regulates the anti-viral immune-responses via mediating alveolar macrophages survival

FBXO6 regulates the anti-viral immune-responses via mediating alveolar macrophages survival

  • J Med Virol. 2022 Oct 10. doi: 10.1002/jmv.28203.
Mengyuan Cen 1 2 Wei Ouyang 1 Xiuhui Lin 1 Xiaohong Du 3 Huiqun Hu 1 Huidan Lu 1 Wanying Zhang 1 Jingyan Xia 4 Xiaofeng Qin 5 6 Feng Xu 1 7
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 2 Department of Respiratory Medicine, Ningbo First Hospital, Ningbo, 315010, China.
  • 3 Institute of Clinical Medicine Research, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, 215153, China.
  • 4 Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 5 Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China.
  • 6 Suzhou Institute of Systems Medicine, Suzhou, 215123, China.
  • 7 Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou, 310053, China.
Abstract

Inducing early Apoptosis in alveolar macrophages is one of the strategies influenza A virus (IAV) evolved to subvert host immunity. Correspondingly, the host mitochondrial protein nucleotide-binding oligomerization domain-like receptor (NLR)X1 is reported to interact with virus polymerase basic protein 1-frame 2 (PB1-F2) accessory protein to counteract virus induced Apoptosis. Herein, we report that one of the F-box proteins, FBXO6, promotes proteasomal degradation of NLRX1, and thus facilitates IAV-induced alveolar macrophages Apoptosis and modulates both macrophage survival and type I interferon (IFN) signaling. We observed that FBXO6-deficient mice infected with IAV exhibited decreased pulmonary viral replication, as well as alleviated inflammatory-associated pulmonary dysfunction and morbidity. Analysis of the lungs of IAV-infected mice revealed markedly reduced leukocyte recruitment but enhanced production of type I IFN in Fbxo6-/- mice. Furthermore, increased type I IFN production and decreased viral replication were recapitulated in FBXO6 knockdown macrophages and was associated with reduced Apoptosis. Through gain- and loss-of-function studies, we found lung resident macrophages but not bone marrow derived macrophages play the key role in the differences FBXO6 signaling pathway brings in the Antiviral immune response. In further investigation, we identified that FBXO6 interacted with and promoted the proteasomal degradation of NLRX1. Together, our results demonstrate that FBXO6 negatively regulates immunity against IAV Infection by enhancing the degradation of NLRX1 and thus impairs the survival of alveolar macrophages and Antiviral immunity of the host. This article is protected by copyright. All rights reserved.

Keywords

Alveolar macrophages; Apoptosis; FBXO6; Influenza A; NLRX1.

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