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

Abstract

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.

Pellino Proteins in Viral Immunity and Pathogenesis

“…Pellino3 may have evolved, at least in part, to regulate certain inflammatory signaling cascades. Through respectively poly- and mono-ubiquitination, Pellino3 modifies TRAF6 (tumor necrosis factor receptor-associated factor-6), TRAF3, and TANK (TRAF family member-associated NF-κB activator) [ 15 , 57 , 58 ]. These ubiquitination events disrupt interactions with downstream signaling factors TBK1 (TANK-binding kinase 1, an activator of IRF3), IRF3, and IRF7, and thus diminish IFNβ induction [ 15 , 57 ].…”