Pellino3 ligase negatively regulates influenza B dependent RIG‐I signalling through downregulation of TRAF3‐mediated induction of the transcription factor IRF3 and IFNβ production

• Published in: Immunology Vol. 169; no. 3; pp. 369 - 383
• Main Authors: Kula, Anna, Makuch, Edyta, Lisowska, Marta, Reniewicz, Patryk, Lipiński, Tomasz, Siednienko, Jakub
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-07-2023
• Subjects: Cell lines; Down-Regulation; Epithelial cells; Epithelium; Humans; Immune response; Immune system; Immunity, Innate; Inflammation; Influenza; Influenza B; influenza B virus; Influenza, Human; Innate immunity; Interferon; interferon beta; Interferon regulatory factor; Interferon regulatory factor 3; Interferon Regulatory Factor-3 - genetics; Interferon Regulatory Factor-3 - metabolism; Molecular modelling; Pattern recognition; Pattern recognition receptors; Pellino3 ligase; Retinoic acid; RIG‐I; Signal transduction; Signaling; TNF Receptor-Associated Factor 3 - genetics; TNF Receptor-Associated Factor 3 - metabolism; TRAF3; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Viral infections; Viruses; β-Interferon; interferon beta; RIG-I; Pellino3 ligase; TRAF3; influenza B virus
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.13637

Viral infection activates the innate immune system, which recognizes viral components by a variety of pattern recognition receptors and initiates signalling cascades leading to the production of pro‐inflammatory cytokines. To date, signalling cascades triggered after virus recognition are not fully characterized and are investigated by many research groups. The critical role of the E3 ubiquitin ligase Pellino3 in antibacterial and antiviral response is now widely accepted, but the precise mechanism remains elusive. In this study, we sought to explore Pellino3 role in the retinoic acid‐inducible gene I (RIG‐I)‐dependent signalling pathway. In this work, the molecular mechanisms of the innate immune response, regulated by Pellino3, were investigated in lung epithelial cells during influenza B virus infection. We used wild‐type and Pellino3‐deficient A549 cells as model cell lines to examine the role of Pellino3 ligase in the type I interferon (IFN) signalling pathway. Our results indicate that Pellino3 is involved in direct ubiquitination and degradation of the TRAF3, suppressing interferon regulatory factor 3 (IRF3) activation and interferon beta (IFNβ) production.
Upon influenza B virus infection, viral dsRNA is recognized by retinoic acid‐inducible gene I, which leads to activation and nuclear translocation of interferon regulatory factor 3 (IRF3). Translocated IRF3 induces the expression of type I IFN. Secreted interferon beta (IFNβ) is recognized by interferon alpha/beta receptor, which activates STAT1. Phosphorylated STAT1 translocates to the cell nucleus, which induces the expression of CXCL10. In WT A549 cells, Pellino3 ligase is involved in direct ubiquitination and degradation of the TRAF3, resulting in suppression of IRF3 phosphorylation and IFNβ production. Reduced secretion of IFNβ results in decreased STAT1 phosphorylation and CXCL10 expression.