Ubiquitin in the activation and attenuation of innate antiviral immunity

Abstract

Viral infection activates danger signals that are transmitted via the retinoic acid-inducible gene 1-like receptor (RLR), nucleotide-binding oligomerization domain-like receptor (NLR), and Toll-like receptor (TLR) protein signaling cascades. This places host cells in an antiviral posture by up-regulating antiviral cytokines including type-I interferon (IFN-I). Ubiquitin modifications and cross-talk between proteins within these signaling cascades potentiate IFN-I expression, and inversely, a growing number of viruses are found to weaponize the ubiquitin modification system to suppress IFN-I. Here we review how host- and virus-directed ubiquitin modification of proteins in the RLR, NLR, and TLR antiviral signaling cascades modulate IFN-I expression.

Figure 1.

The ubiquitin modification system and mechanisms of viral manipulation. (1) Ubiquitin (Ub) expresses as an inactive polyprotein, encoded by the UBB and UBC genes. DUbs cleave this polyprotein into monomers that are activated by the E1-activating enzyme, involving the energy-dependent adenylation of the ubiquitin C-terminal glycine. The ubiquitin-adenylate intermediate (dashed line) converts into a covalent thioester bond (solid line). (2) Ubiquitin transfers to the active site cysteine residue of an E2-conjugating enzyme. (3) The E3 directly or indirectly transfers the E2-bound ubiquitin to a substrate acceptor residue, forming an isopeptide bond. (4) DUbs remodel ubiquitin modifications and antagonize ubiquitin-driven functional outcomes.

Figure 2.

Schematic of the TLR, RLR, and NLR antiviral protein signaling cascades and modes of cross-talk. PRRs (blue) screen the intracellular and extracellular environment for pathogenic motifs. Ligand-activated PRRs bind adaptor proteins (purple) and recruit protein kinases (yellow) and ubiquitin-protein ligases (green). These regulate immune signal transduction to transcription factors (orange) through PTM of signaling cascade proteins. Other regulatory proteins (gray) support or sequester these signaling proteins. Immune signaling scaffolds such as mitochondria typically coordinate these actions. Activated transcription factors translocate into the nucleus and bind to promoter response elements, stimulating appropriate antiviral gene transcription. Blue and green circles represent ubiquitination and phosphorylation, respectively. Black arrows, activation; red lines, deactivation.

Figure 3.

Effect on IFN-I expression of ubiquitin modifications to key RLR cascade proteins and mechanisms of manipulation by human-tropic viruses. Ubiquitin modification site and ubiquitin chain linkage type are shown in blue circles. Ubiquitin modifications that up-regulate or down-regulate IFN-I expression are shown with black or red arrows, respectively. Question marks indicate where the modification site, ubiquitin chain linkage, or modifying E3 are unknown. MATH, meprin and TRAF homology domain (also termed TRAF-C); RoV, rotavirus; SARS-CoV, severe acute respiratory syndrome–coronavirus; TM, transmembrane domain; ULD, ubiquitin-like domain.