The intricate interplay between RNA viruses and NF-κB

Abstract

RNA viruses have rapidly evolving genomes which often allow cross-species transmission and frequently generate new virus variants with altered pathogenic properties. Therefore infections by RNA viruses are a major threat to human health. The infected host cell detects trace amounts of viral RNA and the last years have revealed common principles in the biochemical mechanisms leading to signal amplification that is required for mounting of a powerful antiviral response. Components of the RNA sensing and signaling machinery such as RIG-I-like proteins, MAVS and the inflammasome inducibly form large oligomers or even fibers that exhibit hallmarks of prions. Following a nucleation event triggered by detection of viral RNA, these energetically favorable and irreversible polymerization events trigger signaling cascades leading to the induction of antiviral and inflammatory responses, mediated by interferon and NF-κB pathways. Viruses have evolved sophisticated strategies to manipulate these host cell signaling pathways in order to ensure their replication. We will discuss at the examples of influenza and HTLV-1 viruses how a fascinating diversity of biochemical mechanisms is employed by viral proteins to control the NF-κB pathway at all levels.

Keywords: Influenza virus; Interferon signaling; NF-κB; RNA virus; Signal transduction.

Fig. 1

Sensing of viral RNA and induction of the host cell defense. The inducible aggregation of RLRs, MAVS and the inflammasome is displayed. While NF-κB activation proceeds via TRAF2/6, TRAF3 activates the kinases TBK1 and IKKε. These kinases phosphorylate IRF transcription factors, thus allowing for their dimerization and DNA-binding. Important domains in the proteins are shown in colors. The inflammasome can be also activated upon association with the mitochondrial MAVS protein, but this process is not displayed for the sake of clarity.

Fig. 2

Schematic display of IKK substrates. Arrows point to the different IKKα/IKKβ substrates; the biological functions of the substrates are also indicated.

Fig. 3

Cellular targets inhibited by the IAV protein NS1. The red lines point to the cellular targets that show reduced activity in the presence of NS1.

Fig. 4

Cellular targets regulated by the HTLV-1 Tax-1 protein. The different localizations and interaction partners of Tax-1 are shown; its possible contribution to the induction of the atypical NF-κB pathway is indicated.