PMC

Innate Immune IFN Responses and Caspase-1-Mediated Activation of Cytokines or Cell Death Are Functionally Coupled by Upstream PRRs for Viral DNA
Sensors: cGAS, cGAMP synthase; IFI16, IFN-inducible protein 16; DAI, DNA-dependent activator of IRFs; DDX41, DEAD Asp-Glu-Ala-Asp box polypeptide 41. Adapters and transcription factors: ASC, activating signal cointegrator 1; STING, stimulator of IFN gene; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IRF3, IFN regulatory factor 3.

Individual innate immune stimuli ligate specific TLRs. The specific TLR(s) ligated directly interact with the TBK1 phosphorylation complex to help dictate the specific IRFs that are activated, leading to a stimulus-specific response. Cross-reactivity of innate immune stimuli with other innate immune receptors such as RLRs or DAI can also impact the specificity of the IRFs activated by TBK1. Expression of regulatory molecules including miRNAs may occur within stimulus-specific responses, further feeding back on the pathway.
DAI: DNA-dependent activator of IFN regulatory factors; IRF: Interferon regulatory factor; RLR: RIG-like receptor; TBK: TANK binding kinase 1; TLR: Toll-like receptor.

TLRs, RLRs, CDSs, and helicase complexes can sense PAMPs and MAMPs such as ss/dsRNA, DNA, LPS, and c-di-AMP. Engagement of these sensors converges on activation of IRF3 and IRF7 via the common downstream kinases, TBK1/IKKε in addition to NFκB activation. This leads to the production of IFN-I and other cytokines. The adapter protein IPS-1 (also called MAVS) is required for transferring signals from the RLRs and helicases to IRFs. CDSs, cytosolic DNA sensors; MAMPs, microbe-associated molecular patterns; MAVS, mitochondrial antiviral signaling protein; Pol III, RNA polymerase III; ZBP-1, Z-DNA-binding protein 1 (also called DAI, DNA-dependent activator of IFN-regulatory factors).

The inflammasomes include a superfamily of multi-domain proteins that on ligand binding provide scaffolds for the assembly of large oligomeric complexes resulting in the activation of caspases that then cleave pro-inflammatory cytokines pro-IL-1beta and –IL-18 into the mature form for secretion to promote the immune response. The multiple domains in their structure can include: leucine-rich-repeats (LRR); HIN-200 like DNA binding domains (HIN); Nucleotide binding and oligomerization domain (NACHT or NOD); PYRIN like domains (PYD); and Caspase recruitment domain (CARD). B. Insert: Structural domains of the DNA-dependent activator of IRFs (DAI) [, ].