Post-translational Control of Intracellular Pathogen Sensing Pathways

Abstract

Mammalian cells recognize virus-derived nucleic acids using a defined set of intracellular sensors including the DNA sensors cyclic GMP-AMP (cGAMP) synthase (cGAS) and interferon gamma (IFNγ)-inducible protein 16 (IFI16) as well as viral RNA receptors of the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family. Following innate immune recognition, these sensors launch an immune response that is characterized by the transcriptional upregulation of many antiviral molecules, including proinflammatory cytokines, chemokines, and IFN-stimulated genes. Recent studies have demonstrated that the signal transduction initiated by these sensors is sophisticatedly regulated by post-translational modifications (PTMs) resulting in a robust yet 'tunable' cytokine response to maintain immune homeostasis. Here we summarize recent advances in our understanding of how PTMs and regulatory enzymes control the signaling activity of RLRs, cGAS, and IFI16 as well as their proximal adaptor proteins.

Figure 1

Post-translational Modifications (PTMs) that Modulate the Retinoic Acid-Inducible Gene I (RIG-I)-like receptor (RLR)–Mitochondrial Antiviral Signaling Protein (MAVS) Signaling Pathway. Schematic of the signaling pathway triggered by the intracellular viral double-stranded RNA (dsRNA) sensors RIG-I and melanoma differentiation-associated protein 5 (MDA5) and their shared adaptor MAVS localized at the mitochondrion. Activation of this pathway leads to the gene expression of type I interferons (IFNs) and other proinflammatory cytokines via TANK-binding kinase 1 (TBK1) and IKK family kinases and downstream transcription factors, primarily IRF3 and nuclear factor kappa B (NF-κB). This figure further illustrates the PTMs and responsible enzymes that modulate the signaling activity or protein abundance of RIG-I, MDA5, and MAVS. The details of the post-translational control mechanisms and specific residues modified in RIG-I, MDA5, and MAVS are described in the text. Unbroken arrows indicate direct effects or signaling events. Broken arrows indicate events that are indirect or that have not yet been completely established. Abbreviations: Ac, acetylation; CARD, caspase activation and recruitment domain; CTD, carboxy-terminal domain; P, phosphate; Ub, ubiquitin; K63-(Ub)n, K63-linked ubiquitination; K48-(Ub)n, K48-linked ubiquitination. Red/orange signifies inhibitory PTMs; blue/green indicates positive regulatory PTMs.

Figure 2

Post-translational Modifications that Control Innate Immunity Mediated by Cyclic GMP–AMP (cGAMP) Synthase (cGAS), Interferon Gamma (IFNγ)-Inducible Protein 16 (IFI16), and Stimulator of IFN Genes (STING). This figure illustrates the post-translational modifications and regulatory enzymes that play a critical role in balancing the innate immune response mediated by the intracellular DNA sensors cGAS and IFI16 as well as their adaptor protein STING. Following recognition of viral double-stranded DNA (dsDNA), cGAS produces the second messenger cGAMP, which then binds to and induces STING activation characterized by dimerization and its translocation from the endoplasmic reticulum (ER) to the Golgi and perinuclear sites (not shown). Similarly, in response to viral DNA binding IFI16 oligomerizes and translocates from the nucleus to the cytoplasm to activate STING. The two signals then result in the activation of TANK-binding kinase 1 (TBK1) and IRF3 as well as nuclear factor kappa B (NF-κB), evoking the gene expression of type I IFNs. Many of the described steps in cGAS, IFI16, and STING activation are delicately controlled by regulatory enzymes that mediate the reversible phosphorylation, ubiquitination, glutamylation, or acetylation of these proteins. Unbroken arrows indicate direct effects or signaling events. Broken arrows indicate events that are indirect or that have not yet been completely established. Abbreviations: Ac, acetylation; E, glutamylation; P, phosphate; Ub, ubiquitin; K11-(Ub)n, K11-linked ubiquitination; K27-(Ub)n, K27-linked ubiquitination; K48-(Ub)n, K48-linked ubiquitination; K63-(Ub)n, K63-linked ubiquitination. Red/orange signifies inhibitory PTMs; blue/green/purple indicates positive regulatory PTMs.