Negative Regulation of Cytosolic Sensing of DNA

Abstract

In mammals, cytosolic detection of nucleic acids is critical in initiating innate antiviral responses against invading pathogens (like bacteria, viruses, fungi and parasites). These programs are mediated by multiple cytosolic and endosomal sensors and adaptor molecules (c-GAS/STING axis and TLR9/MyD88 axis, respectively) and lead to the production of type I interferons (IFNs), pro-inflammatory cytokines, and chemokines. While the identity and role of multiple pattern recognition receptors (PRRs) have been elucidated, such immune surveillance systems must be tightly regulated to limit collateral damage and prevent aberrant responses to self- and non-self-nucleic acids. In this review, we discuss recent advances in our understanding of how cytosolic sensing of DNA is controlled during inflammatory immune responses.

Keywords: Auto-inflammation; Infertility; Inflammasome; Interferon; NLRP14; Nucleic acid sensing; Post-translational modifications; RIG-I; STING; TBK1; cGAS.

Fig. 1

Cytosolic sensing of DNA via cGAS/STING. Upon viral infection, cGAS recognizes viral dsDNA and utilizes GTP/ATP to catalyze cGAMP and trigger activation of STING. In addition to foreign DNA, cGAS promotes STING-dependent signal activation in response to nucleosome and micronuclear DNA that results from DNA damage. Following cGAMP binding, STING translocates from the ER to perinuclear-Golgi, and forms a signaling complex with TBK1 (phosphorylation of STING at S-366 occurs after translocation) leading to IRF3-mediated type I IFN production as well as NF-κB (p65)-mediated signaling. Abbreviations: cGAS, cyclic GMP-AMP Synthase; STING, Stimulator of IFN Genes; cGAMP, cyclic GMP-AMP; dsDNA, double-stranded DNA; ER, Endoplasmic Reticulum; TBK1, TANK-Binding Kinase 1; IRF3, Interferon Regulatory Factor 3; P, Phosphorylation.

Fig. 2

Regulation of cGAS/STING-signaling through Post-Translational Modifications (PTMs). Ubiquitin E3 ligases as well as ubiquitin specific proteases (USPs) regulate STING function and localization. In addition, ubiquitin-mediated proteasome pathway can lead to degradation of STING and termination of signaling activation—ULK1 controls STING degradation. Detailed description and identity of targeted residues in cGAS and STING are described in the text. Ub, Ubiquitin; S, SUMOylation; P, Phosphorylation; 11, K11-linked Ub; 27, K27-linked Ub; 33, K33-linked Ub; 48, K48-linked Ub; 63, K63-linked Ub; T4, TTLL (tubulin tyrosine ligase-like enzymes) 4; T6, TTLL6; ULK1, UNC-51-like kinase.

Fig. 3

Intracellular nucleases that modulate cGAS/STING signaling responses: Recognition of self and non-self DNA can augment production of pro-inflammatory genes in virtually all nucleated cells. To prevent an aberrant inflammatory, the three-prime repair exonuclease 1 (TREX1) targets self and non-self DNA for degradation in the cytoplasm, while DNase II plays a similar role in lysosomes. Hydrolysis of cGAMP by ENPP1 also prevents inappropriate activation of STING. Abbreviations: RT, Reverse transcription; HIV-1, Human Immunodeficiency virus-1.

Fig. 4

Viral strategies to evade cytosolic DNA sensing: To escape cytosolic sensing, HIV-1 capsid protein suppresses cGAS-mediated sensing of DNA by recruiting cyclophilin-A (Cyp-A). Other viral proteins, including HTLV-1 Tax protein, HBV polymerase (HBV-Pol), papain-like proteases (PLPs) derived from human coronavirus (HCoV)-NL63, severe acute respiratory syndrome (SARS), and porcine epidemic diarrhea virus (PEDV), interfere K63-linked poly-ubiquitination of STING. E7 and E1A of human papillomavirus 18 (HPV18) and human adenovirus type-5 (hAd5) suppress DNA sensing through direct association with STING. Kaposi sarcoma-associated herpesvirus (KHSV) encodes a viral interferon regulatory factor 1 (vIRF1) to suppress IRF3-mediated production of IFN. The NS2B/NS3 protease of dengue virus (DENV) cleaves human STING at the N-terminal of TM3 region. Finally, murine gammaherpesvirus 68 (MHV68) encodes a de-ubiquitination (DUB) enzyme that contributes to the establishment of latent infection. Abbreviation: HTLV-1, Human T Lymphotropic Virus type-1; HIV-1, Human Immunodeficiency Virus-1; HBV, Hepatitis B Virus; ORF, Open Reading Frame.

Fig. 5

NLRP14-mediated inhibition of cytosolic nucleic acid sensing. Upon activation of STING dependent signaling, conformational rearrangement from inhibitory-form to an active-form of NLRP14 is induced. Targeting of TBK1 for K48-linked poly-ubiquitination is then initiated and results in proteasome dependent degradation of TBK1 and termination of STING dependent as well as RIG-I dependent signaling. Similarly, NLRP14 is targeted for degradation to avoid persistent immunosuppression. Abbreviations: NLRP14, Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing protein 14; PYD, Pyrin domain; NACHT, NAIP (neuronal apoptosis inhibitory protein), CIITA (MHC class II transcription activator), HET-E (incompatibility locus protein from Podospora anserine) and TP1 (telomerase-associated protein), LRR, Leucine-rich repeat; Ub, Ubiquitin; P, Phosphorylation.